Tricyclic compound having acyloxymethoxycarbonyl side chain

ABSTRACT

There are provided a compound represented by the formula (I):wherein X and X&#39; are -N(COOCR&lt;3&gt;R&lt;2&gt;OCOR&lt;1&gt;)-, -O- or the like, R&lt;1 &gt;is alkyl substituted with carbamoyl, lower alkylcarbamoyl, carbamoyloxy, lower alkylcarbamoyloxy, acetylamino or the like, R&lt;2 &gt;and R&lt;3 &gt;are hydrogen or the like, Y and Y&#39; are lower alkyl, lower alkenyl or the like, ring A, ring B and ring C are optionally substituted aromatic carbocycle or optionally substituted heterocycle, W&lt;1&gt;, W&lt;2 &gt;and/or W&lt;3 &gt;are a bond or the like, and V&lt;1 &gt;and V&lt;2 &gt;are a single bond or the like, or a pharmaceutically acceptable salt or a solvate thereof, as well as a pharmaceutical composition containing the present compound.

TECHNICAL FIELD

The present invention relates to a novel compound which is useful as aprodrug, a pharmaceutical composition containing the same and anintermediate therefor. More particularly, the present invention relatesto a novel tricyclic compound having an acyloxymethoxycarbonyl sidechain, an immunosuppressant and an antiallergic agent containing thesame as well as a novel tricyclic compound having the immunosuppressiveactivity and the antiallergic activity and an intermediate therefor.

BACKGROUND ART

Making of prodrugs for pharmaceutical active substances is studied inmany cases for the purpose of improving the physical properties such asthe crystallizability, the stability, the water-solubility and the like,the bioavailability, and duration of the pharmacological activity. Inparticular, although it is desirable to convert amine compounds into aprodrug for the purpose of enhancing the absorbability and thestability, simple amidated prodrugs can not be returned to amines in theliving body and it is said that procedures for converting into a prodrugrequire elaboration.

In WO97/39999 and WO98/04508, it is disclosed that para-terphenylderivatives are effective as an immunosuppressant and an antiallergicagent. In particular, WO98/04508 refers to prodrugs and, moreparticularly, describes conversion of hydroxy compounds into a prodrug.

In JP-A23359/1985, JP-A18747/1986 and WO96/18605, described is a methodof making a prodrug by substituting primary or secondary amines with—COOCR¹R²OCOR³ (R³=alkyl, carboxyalkyl, haloalkyl, carbamylalkyl etc.).In addition, in JP-A503925/1993 and Synthesis (December, 1990,1159-1166), there are described R²SCOOCH₂OCOR¹ (Compound A) andClCOOCH₂OCOR¹ (Compound B) as an intermediate for synthesizing aprodrug. However, it is clearly described therein that Compound B cannot be synthesized from Compound A (wherein R¹ is hydroxyethyl oracetylaminomethyl, and R² is ethyl) according to those methods.

Compounds having the similar skeleton to that of the present compoundand having the immunosuppressive activity or the antiallergic activityare described in WO94/27980, WO95/13067, WO96/15123, WO95/15318,WO96/40659, WO96/40143, WO96/38412, WO96/10012, WO97/24356, WO97/27181,WO97/24324, WO97/44333, WO97/46524, WO98/04508, WO98/24766, WO98/24782,WO98/56785, FR2301250, U.S. Pat. No. 5,593,991, JP-B7368/1972,JP-A91259/1976, JP-A3163/1996, JP-A124571/1997, JP-A71564/1997,JP-A124571/1997, JP-A79993/1999, Bioorganic & Medicinal ChemistryLetters, Vol.5, No.18, p2143-2146(1995), J. Med. Chem., 1974, Vol.17,NO.11, 1177-1181 and the like.

Additionally, liquid crystalline compounds having the similar skeletonto that of the present compound are disclosed in JP-A121225/1983,JP-A87253/1997, JP-A253065/1988, JP-A106864/1986, JP-A106871/1986,JP-A83346/1990, JP-A48760/1997, JP-A31063/1997, WO88/07992 and the like,compounds having the insecticidal or miticidal activity inJP-A193067/1996, compounds having the circulatory disease andpsychosis-treating activity in EP0600717A1, and compounds having thecentral nervous disease-treating activity in WO95/15954.

DISCLOSURE OF INVENTION

An object of the present invention is to provide a novel prodrug of acompound having the immunosuppressive activity and/or the antiallergicactivity.

The present invention provides the following compounds orpharmaceutically acceptable salts thereof or prodrugs thereof.

[1] A compound represented by the formula (I):

(hereinafter, referred to as compound (I))

wherein one of X and X′ is —N(COOCR³R²OCOR¹)—, the other is —(CH₂)s-(wherein s is an integer of 0 to 2), —O—, —NR^(A)— (wherein R^(A) ishydrogen, optionally substituted lower alkyl, lower alkenyl or loweralkylcarbonyl), —N(COOCR³R²OCOR¹)— or —S(O)p- (wherein p is an integerof 0 to 2),

R¹ is lower alkyl substituted with 1 or 2 groups selected from the groupconsisting of —CONH₂, —CONHCH₃, —CONHC₂H₅, —OCONH₂, —OCONHCH₃,—OCONHC₂H₅, —(NHCOCRR′)mNHCOCH₃, —(NHCOCRR′)mNHCOC₂H₅, —CSNH₂,—(OCH₂CH₂)nOH, —OCH₃, —(OCH₂CH₂)nOCH₃, —COCH₃, —COC₂H₅, —OCOCH₃,—OCOC₂H₅, —NHOH, —NHCONH₂, —NHCSNH₂, —NHSO₂CH₃, —N(SO₂CH₃)₂, —O₂NH₂,—SOCH₃, —SO₂CH₃, —OCH₂CONH₂, —OCH₂CON(CH₃)₂, —SO₂N(CH₃)₂, —PO(OCH₃)₂,—NHCSNHC₂H₅, —CH═NNHCONH₂, —CH═NNHCSNH₂, —CH═NNHSO₂CH₃, triazolyl andtetrazolyl (wherein R and R′ are each independently hydrogen or loweralkyl, m is an integer of 0 to 2, and n is an integer of 1 or 2),

R² and R³ are each independently hydrogen or lower alkyl,

Y and Y′ are each independently hydrogen, optionally substituted loweralkyl, optionally substituted lower alkenyl, optionally substitutedlower alkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkenyl, optionally substituted lower alkoxycarbonyl, optionallysubstituted sulfamoyl, optionally substituted amino, optionallysubstituted aryl or optionally substituted 5-membered or 6-memberedheterocycle,

when X is —CH₂—, Y may be optionally substituted lower alkoxy,

when X′ is —CH₂—, Y′ may be optionally substituted lower alkoxy,

when X is —O— or —NR^(A)—, Y may be optionally substituted loweralkylsulfonyl or optionally substituted arylsulfonyl,

when X′ is —O— or —NR^(A)—, Y′ may be optionally substituted loweralkylsulfonyl or optionally substituted arylsulfonyl,

ring A, ring B and ring C are each independently optionally substitutedaromatic carbocycle or optionally substituted 5-membered or 6-memberedheterocycle which may be fused with a benzene ring,

when ring A, ring B and/or ring C are optionally substituted5-membered-heterocycle, W¹, W² and/or W³ represent a bond,

one of V¹ and V² is a single bond, the other is a single bond, —O—,—NH—, —OCH₂—, —CH₂O—, —CH═CH—, —C≡C—, —CH(OR^(B))— (wherein R^(B) ishydrogen or lower alkyl), —CO—, —NHCHR^(C)— or —CHR^(C)NH— (whereinR^(C) is hydrogen or hydroxy),

when both V¹ and V² are a single bond, at least one of ring A, ring Band ring C is optionally substituted aromatic carbocycle, and at leastone is optionally substituted 5-membered or 6-membered heterocycle whichmay be fused with a benzene ring,

[2] a compound represented by the formula (II):

(hereinafter, referred to as compound (II))

wherein one of X and X′ is —N(COOCR³R²OCOR¹)—, and the other is —O—,—NH— or —N(COOCR³R²OCOR¹)—,

Y and Y′ are each independently optionally substituted lower alkyl,optionally substituted lower alkenyl or optionally substituted loweralkynyl,

R¹, R² and R³ have the same meanings as those for [1],

ring A and ring C are each independently optionally substituted benzenering or optionally substituted 6-membered heterocycle containing 1 or 2heteroatoms, at least one of them being 6-membered heterocycle,

R⁸, R⁹, R¹⁰ and R¹¹ are each independently hydrogen, halogen, hydroxy,optionally substituted lower alkyl, optionally substituted lower alkoxy,optionally substituted lower alkenyl, optionally substituted loweralkenyloxy, optionally substituted cycloalkyloxy, optionally substitutedacyloxy, carboxy, optionally substituted lower alkoxycarbonyl,optionally substituted lower alkenyloxycarbonyl, optionally substitutedlower alkylthio, optionally substituted lower alkenylthio, optionallysubstituted amino, optionally substituted carbamoyl, guanidino, nitro,optionally substituted lower alkylsulfonyl, optionally substituted loweralkylsulfonyloxy, optionally substituted arylsulfonyl or optionallysubstituted arylsulfonyloxy,

[3] a compound represented by the formula (III):

(hereinafter, referred to as compound (III))

wherein X is —NH— or —N(COOCR³R²OCOR¹)—, X′ is —O—, —NH— or—N(COOCR³R²OCOR¹)—, at least one of X and X′ being —N(COOCR³R²OCOR¹)—,

Y and Y′ are each independently optionally substituted lower alkyl oroptionally substituted lower alkenyl,

R¹, R² and R³ have the same meanings as those for [1],

R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently hydrogen,halogen, hydroxy, optionally substituted lower alkyl, optionallysubstituted lower alkoxy, optionally substituted lower alkenyl,optionally substituted lower alkenyloxy, carboxy, optionally substitutedlower alkoxycarbonyl or optionally substituted amino,

ring C is pyridine or pyrimidine, each being optionally substituted withlower alkyl,

[4] a compound described in any one of [1] to [3], wherein R¹ is C1 toC3 alkyl substituted with 1 or 2 groups selected from the groupconsisting of —CONH₂, —OCONH₂ and —(NHCOCRR′)mNHCOCH₃,

[5] a compound described in [3], wherein R⁴ and R⁵ are eachindependently hydrogen or halogen,

[6] a compound described in [3], wherein R⁶ and R⁷ are both hydrogen,

[7] a compound described in [2] or [3], wherein R⁸ and R¹¹ are eachindependently hydrogen, hydroxy or lower alkyl,

[8] a compound described in [2] or [3], wherein R⁹ and R¹⁰ are eachindependently lower alkyl, lower alkoxy or lower alkoxycarbonyl,

[9] a compound described in any one of [1] to [3], wherein X′ is —O—,

[10] a compound described in [3], wherein X is —NH— or—N(COOCR³R²OCOR¹)—, X′ is —O—, —NH— or —N(COOCR³R²OCOR¹)—, at least oneof X and X′ being —N(COOCR³R²OCOR¹)—,

R¹ is C1 to C3 alkyl substituted with 1 or 2 groups selected from thegroup consisting of —CONH₂, —OCONH₂ and —(NHCOCRR′)mNHCOCH₃, R² and R³are hydrogen or C1 to C3 alkyl,

Y and Y′ are each independently lower alkyl optionally substituted withhalogen or lower alkenyl optionally substituted with halogen, R⁴ and R⁵are each independently hydrogen or halogen, R⁶ and R⁷ are both hydrogen,R⁸ and R¹¹ are each independently hydrogen, hydroxy or lower alkyl, R⁹and R¹⁰ are each independently lower alkyl, lower alkoxy or loweralkoxycarbonyl, and ring C is pyridine or pyrimidine, each beingoptionally substituted with lower alkyl,

[11] a compound described in any one of [1], [2], [3] and [10], whereinY and Y′ are both prenyl,

[12] a compound described in [3] or [4], wherein ring C is

R⁴and R⁵ are each independently hydrogen, halogen or lower alkoxy, R⁶and R⁷ are each independently hydrogen, halogen or lower alkyl, R⁸ andR¹¹ are both lower alkyl, or one of them is lower alkyl and the other ishydrogen or lower alkoxy, R⁹ and R¹⁰ are both hydrogen, lower alkyl orlower alkoxy, and one of —X—Y and —X′—Y′ is—N(COOCR³R²OCOR¹)-(optionally substituted lower alkyl or optionallysubstituted lower alkenyl), and the other is prenyloxy or prenylamino,

[13] a compound described in [3] or [4], wherein ring C is

wherein X has the same meaning as that for [3], a salt or solvatethereof.

Another embodiment of the present invention provides a pharmaceuticalcomposition containing a compound described in any one of [1] to [13] ora pharmaceutically acceptable salt or solvate thereof, moreparticularly, an immunosuppressive agent or an antiallergic agent.Furthermore, the present invention provides a method for inhibiting animmunoreaction, or a method for treating or preventing allergicdiseases, which comprises administering a compound (I). Further, thepresent invention provides use of a compound for preparing a medicamentfor inhibiting an immunoreaction, or treating or preventing allergicdiseases.

Another embodiment of the present invention provides the followingcompounds useful as an intermediate for compounds (I) and (II):

a compound represented by the formula (VIIb′):

wherein one of R⁴ and R⁵ is hydrogen, the other is halogen, R⁸ and R¹¹are each independently hydrogen, hydroxy or lower alkyl, R⁹ and R¹⁰ areeach independently lower alkyl, lower alkoxy or lower alkoxycarbonyl, L′is dihydroxyboryl, di-lower alkylboryl or di-lower alkoxyboryl, apharmaceutically acceptable salt or solvate thereof, and

a compound represented by the formula (VIb′):

wherein ring C is pyridine ring optionally substituted with lower alkylor pyrimidine ring optionally substituted with lower alkyl, T isprotected hydroxy, lower alkylthio or arylthio, Z′ is dihydroxyboryl,di-lower alkylboryl or di-lower alkoxyboryl, and s is an integer of 0 to2, or pharmaceutically acceptable salt or solvate thereof.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a view showing the concentration of a parent compound (II-1)in plasma when compound (I-1) is administered.

FIG. 2 is a view showing the concentration of a parent compound (II-4)in plasma when a compound (I-163) or a parent compound (II-4) isadministered.

FIG. 3 is a view showing the concentration of a parent compound (II-1)in plasma when a compound (I-16) or a parent compound (II-1) isadministered.

BEST MODE FOR CARRYING OUT THE INVENTION

As used herein, the “halogen” includes fluorine, chlorine, bromine andiodine. In particular, fluorine and chlorine are preferable.

The “lower alkyl” includes a straight or branched C1 to C10, preferablyC1 to C8, more preferably C1 to C5, and most preferably C1 to C3 alkyl.Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl,isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl.Most preferable is methyl.

The “C1 to C5 alkyl” includes a straight or branched alkyl, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl and neopentyl.

The “C1 to C3 alkyl” includes a straight or branched alkyl, for example,methyl, ethyl, n-propyl and isopropyl.

Examples of a substituent of the “optionally substituted lower alkyl”include halogen; hydroxy; lower alkoxy optionally substituted with loweralkoxy; acyl; acyloxy; carboxy; lower alkoxycarbonyl; mercapto; loweralkylthio; amino optionally substituted with hydroxy, lower alkyl oroptionally substituted acyl, imino optionally substituted with hydroxy,lower alkoxy, carboxy-lower alkoxy, aryl-lower alkoxy or 5-membered or6-membered heterocycle; hydrazono optionally substituted with carbamoylor lower alkoxycarbonyl; carbamoyl optionally substituted with loweralkyl or amino; thiocarbamoyl optionally substituted with lower alkyl;cycloalkyl optionally substituted with lower alkyl or lower alkoxy;cycloalkenyl optionally substituted with lower alkyl; cyano; phenyloptionally substituted with 1 or more of hydroxy, lower alkyl, carboxy,lower alkoxycarbonyl and lower alkoxy; 5-membered or 6-memberedheterocycle optionally substituted with lower alkyl and optionally fusedwith a benzene ring. In this case, any position may be substituted with1 or more of these substituents. Preferable is a non-substituted loweralkyl.

A lower alkyl part of the “lower alkoxy” is the same as that for theabove “lower alkyl”.

Examples of a substituent of the “optionally substituted lower alkoxy”include halogen; hydroxy; lower alkoxy optionally substituted withacyloxy; acyl; acyloxy; carboxy; lower alkoxycarbonyl; lower alkylthio;amino optionally substituted with lower alkyl; phenyl optionallysubstituted with lower alkyl or lower alkoxy; heterocycle; heterocycliccarbonyloxy. Preferable is a non-substituted lower alkoxy.

A lower alkyl part for the “lower alkylthio”, “lower alkoxycarbonyl”,“lower alkylsulfonyl”, “lower alkylsulfonyloxy”, “lower alkylsulfinyl”,“lower alkylcarbamoyl”, “lower alkylcarbamoyloxy” and “loweralkylenedioxy” is the same as that for the above “lower alkyl”.

A substituent for the “optionally substituted lower alkoxycarbonyl”,“optionally substituted lower alkylsulfonyl”, “optionally substitutedlower alkylsulfonyloxy”, “optionally substituted lower alkylsulfinyl”and “optionally substituted lower alkylthio” is the same as that for theabove “optionally substituted lower alkoxy”.

The “lower alkenyl” includes a straight or branched C2 to C10,preferably C2 to C8, more preferably C3 to C6 alkenyl having 1 or moredouble bonds at an arbitrary position. More particularly, examplesthereof include vinyl, propenyl, isopropenyl, butenyl, isobutenyl,prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl,isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl and decenyl. Asubstituent for the “optionally substituted lower alkenyl”, is the sameas that for the above “optionally substituted lower alkoxy”.

A lower alkenyl part of the “lower alkenyloxy”, “loweralkenyloxycarbonyl” and “lower alkenylthio” is the same as that for theabove “lower alkenyl”. A substituent of the “optionally substitutedlower alkenyloxy”, “optionally substituted lower alkenyloxycarbonyl” and“optionally substituted lower alkenylthio” is as same as that for theabove “optionally substituted lower alkoxy”.

The “lower alkynyl” includes a straight or branched C2 to C10,preferably C2 to C8, and more preferably C3 to C6 alkynyl, for example,ethynyl, propynyl (2-propynyl etc.), butynyl (2-butynyl etc.), pentynyl,hexynyl, heptynyl, octynyl, nonynyl and decynyl. These have 1 or moretriple bonds at an arbitrary position and, further, may have a doublebond.

A substituent of the “optionally substituted lower alkynyl” is the sameas that for the above “optionally substituted lower alkoxy”.

The “acyl” includes a straight or branched C1 to C10, more preferably C1to C6, most preferably C1 to C4 alkylcarbonyl, a straight or branched C3to C10, more preferably C3 to C6, most preferably C3 to C4alkenylcarbonyl, and C4 to C9, preferably C4 to C7 cycloalkylcarbonyland arylcarbonyl. More particularly, examples thereof include formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl,acryloyl, propioloyl, methacryloyl, crotonoyl, cyclopropylcarbonyl,cyclohexylcarbonyl, cyclooctylcarbonyl and benzoyl. In particular,acetyl is preferable.

A substituent of the “optionally substituted acyl” is the same as thatfor the above “optionally substituted lower alkoxy”, andcycloalkylcarbonyl and arylcarbonyl may further have lower alkyl as asubstituent.

An acyl part of the “acyloxy” is the same as that for the above “acyl”,and a substituent of the “optionally substituted acyloxy” is the same asthat for the above “optionally substituted acyl”.

The “cycloalkyl” is a C3 to C6 carbocycle and includes, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

Examples of a substituent of the “optionally substituted cycloalkyl”include lower alkyl, halogen, hydroxy, carboxy, lower alkoxycarbonyl,lower alkoxy, lower alkylenedioxy, imino optionally substituted withlower alkoxy, aryl and 5-membered or 6-membered heterocycle. 1 or morearbitrary positions may be substituted.

The “cycloalkenyl” includes the above cycloalkyl having 1 or more doublebonds at an arbitrary position in the ring, for example, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl and cyclohexadienyl.

A substituent of the “optionally substituted cycloalkenyl” is the sameas that for the above “cycloalkyl”.

Examples of a substituent of the “optionally substituted amino” includeoptionally substituted lower alkyl {wherein the substituent is loweralkoxy, cycloalkyl, optionally substituted amino (the substituent islower alkyl, phenyl etc.), optionally substituted aryl (the substituentis lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl) orheterocycle}; lower alkylidene; lower alkenyl; lower alkynyl;cycloalkyl; aryl optionally substituted with lower alkyl, carboxy, acylor lower alkoxycarbonyl; sulfamoyl optionally substituted with loweralkyl; lower alkoxycarbonyl; lower alkylsulfonyl; amino optionallysubstituted with lower alkyl or lower alkylidene and the like.

The “optionally substituted imino” includes substituted imino andnon-substituted imino, and a substituent therefor is the same as thatfor the above “optionally substituted amino”.

The “optionally substituted carbamoyl” includes carbamoyl optionallysubstituted with lower alkyl, lower alkenyl, lower alkynyl or the like.

The “optionally substituted sulfamoyl” includes sulfamoyl optionallysubstituted with lower alkyl, lower alkenyl, lower alkynyl or the like.

The “aromatic carbocycle” includes benzene ring, naphthalene ring,anthracene ring and phenanthrene ring. In particular, benzene ring ispreferable.

In addition, the “aromatic carbocycle” may be fused with anothercarbocycle, and examples thereof include indane ring, indene ring anddihydronaphthalene ring.

The “aryl” includes phenyl, naphthyl, anthryl and phenanthryl. Inparticular, phenyl is preferable. In addition, the “aryl” may be fusedwith another carbocycle, wherein a bonding radical(s) may be located atany positions. Examples thereof include indanyl, indenyl,dihydronaphthyl and the like.

Examples of a substituent for the “optionally substituted aromaticcarbocycle” and “optionally substituted aryl” include halogen; hydroxy;lower alkyl optionally substituted with halogen or carboxy; lower alkoxyoptionally substituted with halogen, aryl, heteroaryl or lower alkoxy;lower alkenyl; lower alkynyl; cycloalkyl; lower alkenyloxy; loweralkynyloxy; cycloalkoxy; acyl; acyloxy; carboxy; lower alkoxycarbonyl;lower alkenyloxycarbonyl; lower alkylthio; lower alkynylthio; aminooptionally substituted with lower alkyl, cycloalkyl-lower alkyl,heteroaryl-lower alkyl, lower alkenyl, cycloalkyl, acyl optionallysubstituted with halogen, lower alkoxycarbonyl, or lower alkylsulfonyl;guanidino; nitro; lower alkylsulfonyl; dihydroxyboryl; loweralkylsulfonyloxy optionally substituted with halogen; arylsulfonyl;arylsulfonyloxy; aryl; and 5-membered or 6-membered heterocycle. 1 ormore arbitrary positions may be substituted with these substituents.Preferable are halogen; hydroxy; lower alkyl optionally substituted withhalogen; lower alkoxy optionally substituted with aryl or lower alkoxy;lower alkenyloxy; acyloxy; lower alkylthio; amino optionally substitutedwith lower alkyl, lower alkenyl, acyl optionally substituted withhalogen, or lower alkylsulfonyl; nitro; lower alkylsulfonyl; loweralkylsulfonyloxy optionally substituted with halogen; andarylsulfonyloxy.

An aryl part for the “arylsulfonyl” and “arylsulfonyloxy” is the same asthat for the above “aryl”. In particular, phenyl is preferable. Asubstituent of the “optionally substituted arylsulfonyl” is the same asthat for the above “optionally substituted aryl”. In particular,non-substituted is preferable.

The “5-membered or 6-membered heterocycle” includes 5-membered or6-membered heterocycles containing 1 or more heteroatoms selected fromO, S and N in the ring, for example, aromatic heterocycles such aspyrrole ring, imidazole ring, pyrazole ring, pyridine ring, pyridazinering, pyrimidine ring, pyrazine ring, triazole ring, triazine ring,isoxazole ring, oxazole ring, oxadiazole ring, isothiazole ring,thiazole ring, thiadiazole ring, furan ring and thiophene ring, andnon-aromatic heterocycles such as tetrahydropyrane ring, dihydropyridinering, dihydropyridazine ring, dihydropyrazine ring, dioxane ring,oxathiolane ring, thiane ring, pyrrolidine ring, pyrroline ring,imidazolidine ring, imidazolidine ring, pyrazolidine ring, pyrazolinering, piperidine ring, piperazine ring and morpholine ring.

The “5-membered or 6-membered heterocycle containing 1 or 2 heteroatoms”includes aromatic heterocycles such as pyrrole ring, imidazole ring,pyrazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazinering, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring,furan ring and thiophene ring, and non-aromatic heterocycles such asdioxane ring, oxathiolane ring, thiane ring, dihydropyridine ring,pyrrolidine ring, pyrroline ring, imidazolidine ring, imidazoline ring,pyrazolidine ring, pyrazoline ring, piperidine ring, piperazine ring andmorpholine ring, among the above “5-membered or 6-membered heterocycle”.In particular, aromatic heterocycles are preferable.

Examples of the “5-membered or 6-membered heterocycle” in ring A, ring Bor ring C include preferably 2,5-pyridinediyl and 2,5-pyrimidinediyl.

Examples of the “5-membered or 6-membered heterocycle” in Y includepreferably 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1,2-dihydropyridyl, 2,3-dihydropyridazinyl, 1,2-dihydropyrazinyl and thelike.

Examples of the “5-membered or 6-membered heterocycle which may be fusedwith a benzene ring” include heterocycles exemplified for the above“5-membered or 6-membered heterocycle”, as well as indole ring,isoindole ring, benzimidazole ring, indazole ring, cinnoline ring,phthalazine ring, quinazoline ring, benzisoxazole ring, benzoxazolering, benzoxadiazole ring, benzothiazole ring, benzisothiazole ring,benzofuran ring, benzothiophene ring, benzotriazole ring, isobenzofuranring, indoline ring, isoindoline ring and chromene ring.

Examples of a substituent for the “optionally substituted 5-membered or6-memberdsheterocycle” and “optionally substituted 5-membered or6-membered heterocycle which may be fused with a benzene ring” includehalogen; hydroxy; lower alkyl optionally substituted with hydroxy oracyloxy; lower alkoxy optionally substituted with halogen, aryl or5-membered or 6-membered heterocycle; lower alkenyl; lower alkenyloxy;lower alkynyl; lower alkynyloxy; acyloxy; carboxy; lower alkoxycarbonyl;mercapto; lower alkylthio; lower alkenylthio; amino optionally mono- ordi-substituted with halogen, optionally substituted lower alkyl (thesubstituent is cycloalkyl or 5-membered or 6-membered heterocycle), acyloptionally substituted with halogen, lower alkenyl, cycloalkyl or loweralkylsulfonyl; imino optionally substituted with lower alkylsulfonyl;nitro; lower alkylsulfonyl; aryl; 5-membered or 6-membered heterocycle;oxo; and oxide. 1 or more arbitrary positions may be substituted.

A substituent for the “optionally substitute 5-membered. or 6-memberedheterocycle containing 1 or 2 heteroatoms” is the same as that describedabove. In particular, heterocycle substituted with lower alkyl ornon-substituted heterocycle is preferable.

“When ring A, ring B and/or ring C is (are) optionally substituted5-membered heterocycle, W¹, W² and/or W³ represents (or represent) abond” means that when ring A is 5-membered heterocycle, W¹ represents abond, and positions of V¹ and X binding to ring A are as follows:

Similarly, when ring B or ring C is 5-membered heterocycle, W² or W³represents a bond, respectively and positions of V¹, V² and X′ forbinding are as follows:

X, X′, V¹ or V² may be connected to a heteroatom which is a constituentatom for ring A, ring B or ring C, respectively.

Examples of a pharmaceutically acceptable salt for a compound (I), acompound (II) and a compound (III) (hereinafter, referred to as presentcompound) in the present specification include salts of a mineral acidsuch as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid,hydrofluoric acid and hydrobromic acid; salts of an organic acid such asformic acid, acetic acid, tartaric acid, lactic acid, citric acid,fumaric acid, maleic acid and succinic acid; salts of an organic basesuch as ammonium, trimethylammonium and triethylammonium; salts of analkali metal such as sodium, potassium and the like and salts of analkaline earth metal such as calcium, magnesium and the like.

The present invention includes a solvate of the present compound. Onemolecule of the compound may be coordinated with an arbitrary number ofsuitable organic solvents or water molecules. Preferably, the solvate isa hydrate. In addition, the present invention includes all stereoisomers(such as atrop isomer) of the present compound.

The present compound has the great characteristic that it is convertedinto a prodrug by substituting an amino group of an amino-substitutedtricyclic compound with an acyloxymethoxycarbonyl group substituted witha nonionic and hydrophilic group. The “nonionic and hydrophilic group”includes a group which is not dissociated into ions in a solution andcan reduce the lipophilicity (hydrophobicity) of a parent compound toimpart the hydrophilicity thereto. The hydrophilic group includes agroup having a negative hydrophobic substituent constant n obtained by amethod described in Journal of Medicinal Chemistry, 1973, vol. 16,No.11, 1207-1216 and Journal of Medicinal Chemistry, 1977, vol.20, No.20, 304-306, preferably a group having π of −0.5 or less. Thehydrophobic substituent constant can be obtained by the followingequation:

π=logP_(X-C6H5)−^(logP) _(benzene)

wherein P_(X-C6H5) is a distribution coefficient of benzene substitutedwith a substituent X for which π is desired to be obtained, betweenwater-octanol, and P_(benzene) is a distribution coefficient of benzenebetween water-octanol (logP_(benzen)=2.13).

Examples thereof include —CONH₂, —CONHCH₃, —CONHC₂H₅, —OCONH₂,—OCONHCH₃, —OCONHC₂H₅, —(NHCOCRR′)mNHCOCH₃, —(NHCOCRR′)mNHCOC₂H₅,—CSNH₂, —(OCH₂CH₂)nOH, —OCH₃, —(OCH₂CH₂)nOCH₃, —COCH₃, —COC₂H₅, —OCOCH₃,—OCOC₂H₅, —NHOH, —NHCONH₂, —NHCSNH₂, —NHSO₂CH₃, —N(SO₂CH₃)₂, —SO₂NH₂,—SOCH₃, —SO₂CH₃, —OCH₂CONH₂, —OCH₂CON(CH₃)₂, —SO₂N(CH₃)₂, —PO(OCH₃)₂,—NHCSNHC₂H₅, —CH═NNHCONH₂, —CH═NNHCSNH₂, —CH═NNHSO₂CH₃, triazolyl andtetrazolyl (R and R′ are each independently hydrogen or lower alkyl, mis an integer of 0 to 2, and n is an integer of 1 or 2).

When an amino group of an amino-substituted tricyclic compound issubstituted with a group outside a scope of the present invention, thesufficient effects as a prodrug can not be obtained.

For example, when the amino group is simply substituted with acyl oralkoxycarbonyl, the resulting compound is stable and is not returned toan active form in the living body. When the amino group is substitutedwith aminoacyl or carboxyacyl, the resulting compound has the reducedlipophilicity but is not returned to an active form in the living body.

In addition, when the amino group is substituted with non-substitutedacyloxyalkoxycarbonyl, the resulting compound has the high lipophilicityand is difficult to be absorbed into the living body.

When the amino group is substituted with hydroxy-substitutedacyloxymethoxycarbonyl, the resulting compound has a low melting pointand is difficult to be formulated into preparations.

A compound wherein the amino group is substituted withacyloxymethoxycarbonyl substituted with an ionic hydrophilic group suchas carboxy and dialkylamino can obtain improved effects such as thehydrophilicity but is hardly returned to an active form in the livingbody. In addition, every such the compound has problems that it has thelow yield, is not crystallized, and is inferior in the chemicalstability leading to difficulty in formulation into preparations and,thus, the compound can not be put into practice industrially.

A compound wherein the amino group is substituted withacyloxymethoxycarbonyl substituted with an ionic hydrophilic group suchas phosphate group and sulfonate group is difficult to be synthesized,there remains a problem for industrial utilization.

Consequently, the present invention is characterized in a combination ofan amino-substituted terphenyl compound and an acyloxymethoxycarbonylgroup substituted with the aforementioned groups.

Every compound (I) is a prodrug for a compound having theimmunosuppressive and/or antiallergic activity and, inter alia, thefollowing compounds are particularly preferable.

1) a compound wherein one of X and X′ is —N(COOCR³R²OCOR¹)— and theother is —O—, —NH— or —N(COOCR³R²OCOR¹)—, and R¹, R² and R³ have thesame meanings as those for [1] (hereinafter, X and X′ are referred to asX1),

a compound wherein X is —NH— or —N(COOR³R²OCOR¹)—, X′ is —O— or—N(COOR³R²OCOR¹)—, at least one of them is —N(COOR³R²OCOR¹)—, and R¹, R²and R³ have the same meanings as those for [1] (hereinafter, X and X′are referred to as X2),

a compound wherein X is —N(COOR³R²OCOR¹)—, X′ is —O— or—N(COOR³R²OCOR¹)—, R¹ is lower alkyl substituted with 1 or 2 groupsselected from the group consisting of —CONH₂, —CONHCH₃, —CONHC₂H₅,—OCONH₂, —OCONHCH₃, —OCONHC₂H₅, —NHCOCH₃, —NHCOCH₂NHCOCH₃,—(NHCOCH₂)₂NHCOCH₃ and —NHCOCH(Me)NHCOCH₃, and R² and R³ are eachindependently hydrogen or lower alkyl (hereinafter, X and X′ arereferred to as X3),

a compound wherein X is —N(COOR³R²OCOR¹)—, X′ is —O—, R¹ is lower alkylsubstituted with 1 or 2 groups selected from the group consisting of—CONH₂, —OCONH₂, —NHCOCH₃ and —NHCOCH₂NHCOCH₃, and R² and R³ are bothhydrogen (hereinafter, X and R′ are referred to as X4),

a compound wherein X is —N(COOCR³R²OCOR¹)—, X′ is —O—, R¹ is (i) C1 toC3 alkyl substituted with —CONH₂ and/or —NHCOCH₃, or (ii) C1 to C3 alkylsubstituted with NHCOCH₂NHCOCH₃, and R² and R³ are both hydrogen(hereinafter, X and X′ are referred to as X5),

2) a compound wherein Y and Y′ are each independently optionallysubstituted lower alkyl, optionally substituted lower alkenyl oroptionally substituted lower alkynyl(hereinafter, Y and Y′ are referredto as Y1),

a compound wherein Y and Y′ are each independently optionallysubstituted lower alkyl, optionally substituted lower alkenyl oroptionally substituted lower alkynyl(wherein the substituent is halogen;hydroxy; lower alkoxy; acyl; acyloxy; carboxy; lower alkoxycarbonyl;lower alkylthio; amino optionally substituted with hydroxy, lower alkylor acyl; carbamoyl optionally substituted with lower alkyl or amino;cycloalkyl optionally substituted with lower alkyl or lower alkoxy;cycloalkenyl optionally substituted with lower alkyl; cyano; phenyloptionally substituted with 1 or more of hydroxy, lower alkyl, carboxy,lower alkoxycarbonyl or lower alkoxy; 5-membered or 6-memberedheterocycle optionally substituted with lower alkyl)(hereinafter, Y andY′ are referred to as Y2),

a compound wherein Y and Y′ are each independently optionallysubstituted lower alkyl or optionally substituted lower alkenyl (whereinthe substituent is halogen; hydroxy; lower alkoxy; acyl; carboxy; loweralkoxycarbonyl; amino optionally substituted with lower alkyl; carbamoyloptionally substituted with lower alkyl; cycloalkyl; phenyl; 5-memberedor 6-membered heterocycle)(hereinafter, Y and Y′ are referred to as Y3),

a compound wherein Y and Y′ are each independently lower alkyl or loweralkenyl (hereinafter, Y and Y′ are referred to as Y4),

a compound wherein Y and Y′ are each independently lower alkenyl(hereinafter, Y and Y′ are referred to as Y5),

3) a compound wherein ring A is optionally substituted benzene ring oroptionally substituted 6-membered heterocycle (hereinafter, ring A isreferred to as A1),

a compound wherein ring A is optionally substituted benzene ring or6-membered heterocycle containing 1 or 2 heteroatoms (hereinafter, ringA is referred to as A2),

a compound wherein ring A is optionally substituted benzene ring(hereinafter, ring A is referred to as A3),

a compound wherein ring A is

R⁴, R⁵, R⁶and R⁷are each independently hydrogen, halogen, hydroxy,optionally substituted lower alkyl, optionally substituted lower alkoxy,optionally substituted lower alkenyl, optionally substituted loweralkenyloxy, carboxy, optionally substituted lower alkoxycarbonyl oroptionally substituted amino (hereinafter, ring A is referred to as A4),

a compound wherein ring A is

R⁴, R⁵, R⁶ and R⁷ are each independently hydrogen, halogen, lower alkyl,lower alkoxy or lower alkoxycarbonyl (hereinafter, ring A is referred toas A5),

a compound wherein ring A is

R⁴ and R⁵ are each independently hydrogen, halogen or lower alkoxy, R⁶and R⁷ are each independently hydrogen, halogen or lower alkyl(hereinafter, ring A is referred to as A6),

a compound wherein ring A is

R⁴, R⁵ ₁ R⁶ and R⁷ are each independently hydrogen or halogen(hereinafter, ring A is referred to as A7),

4) a compound wherein ring B is benzene ring (hereinafter, ring B isreferred to as B1),

a compound wherein ring B is

R⁸, R⁹, R¹⁰ and R¹¹ are each independently hydrogen, halogen, hydroxy,optionally substituted lower alkyl, optionally substituted lower alkoxy,optionally substituted lower alkenyl, optionally substituted loweralkenyloxy, carboxy, optionally substituted lower alkoxycarbonyl oroptionally substituted amino (hereinafter, ring B is referred to as B2),

a compound wherein ring B is

R⁸, R⁹, R¹⁰ and R¹¹ are each independently hydrogen, halogen, hydroxy,lower alkyl, lower alkoxy or lower alkoxycarbonyl (hereinafter, ring Bis referred to as B3),

a compound wherein ring B is

R⁸, R⁹, R¹⁰ and R¹¹ are each independently hydrogen, hydroxy, loweralkyl or lower alkoxy (hereinafter, ring B is referred to as B4),

a compound wherein ring B is

R⁸ and R¹¹ are each independently hydrogen, hydroxy or lower alkyl, R⁹and R¹⁰ are each independently lower alkyl, lower alkoxy or loweralkoxycarbonyl (hereinafter, ring B is referred to as B5),

a compound wherein ring B is

R⁸ and R¹¹ are both lower alkyl, or one of them is lower alkyl and theother is hydrogen or lower alkoxy, and R⁹ and R¹⁰ are both hydrogen,lower alkyl or lower alkoxy (hereinafter, ring B is referred to as B6),

a compound wherein ring B is

(hereinafter, ring B is referred to as B7),

a compound wherein ring B is

(hereinafter, ring B is referred to as B8),

5) a compound wherein ring C is optionally substituted benzene ring oroptionally substituted 6-membered heterocycle (hereinafter, ring C isreferred to as C1),

a compound wherein ring C is optionally substituted benzene ring oroptionally substituted 6-heterocycle containing 1 or 2 heteroatoms(hereinafter, ring C is referred to as C2),

a compound wherein ring C is optionally substituted 6-memberedheterocycle containing 1 or 2 N atoms (hereinafter, ring C is referredto as C3),

a compound wherein ring C is 6-membered heterocycle optionallysubstituted with halogen, hydroxy, optionally substituted lower alkyl,optionally substituted lower alkoxy, optionally substituted loweralkenyl, optionally substituted lower alkenyloxy, carboxy, optionallysubstituted lower alkoxycarbonyl or 6-membered hetero cycle containing 1or 2 N atoms which may be substituted with optionally substitutedamino(hereinafter, ring C is referred to as C4),

a compound wherein ring C is pyridine or pyrimidine optionally eachsubstituted with halogen, hydroxy, lower alkyl, lower alkoxy or loweralkoxycarbonyl (hereinafter, ring C is referred to as C5),

a compound wherein ring C is pyridine or pyrimidine optionally eachsubstituted with lower alkyl (hereinafter, ring C is referred to as C6),

a compound wherein ring C is non-substituted pyridine (hereinafter, ringC is referred to as C7),

a compound wherein ring C is

(hereinafter, ring C is referred to as C8),

6) a compound wherein V¹ and V² are both a single bond,

7) a compound wherein a combination of X and X′, Y and Y′, ring A, ringB and ring C is as follows, and V¹ and V² are both a single bond,

(X2, Y3, A3, B2, C3), (X2, Y3, A3, B2, C5), (X2, Y3, A3, B2, C6), (X2,Y3, A3, B3, C3), (X2, Y3, A3, B3, C5), (X2, Y3, A3, B3, C6), (X2, Y3,A3, B5, C3), (X2, Y3, A3, B5, C5), (X2, Y3, A3, B6, C5), (X2, Y3, A3,B7, C5), (X2, Y3, A3, B5, C6), (X2, Y3, A3, B5, C7), (X2, Y3, A5, B2,C3), (X2, Y3, A5, B2, C5), (X2, Y3, A5, B2, C6), (X2, Y3, A5, B3, C3),(X2, Y3, A5, B3, C5), (X2, Y3, A5, B3, C6), (X2, Y3, A5, B5, C3), (X2,Y3, A5, B5, C5), (X2, Y3, A5, B6, C5), (X2, Y3, A5, B7, C5), (X2, Y3,A5, B5, C6), (X2, Y3, A5, B5, C7), (X2, Y3, A7, B2, C3), (X2, Y3, A7,B2, C5), (X2, Y3, A7, B2, C6), (X2, Y3, A7, B3, C3), (X2, Y3, A7, B3,C5), (X2, Y3, A7, B3, C6), (X2, Y3, A7, B5, C3), (X2, Y3, A7, B5, C5),(X2, Y3, A7, B6, C5), (X2, Y3, A7, B7, C5), (X2, Y3, A7, B5, C6), (X2,Y3, A7, B5, C7), (X2, Y4, A3, B2, C3), (X2, Y4, A3, B2, C5), (X2, Y4,A3, B2, C6), (X2, Y4, A3, B3, C3), (X2, Y4, A3, B3, C5), (X2, Y4, A3,B3, C6), (X2, Y4, A3, B5, C3), (X2, Y4, A3, B5, C5), (X2, Y4, A3, B6,C5), (X2, Y4, A3, B7, C5), (X2, Y4, A3, B5, C6), (X2, Y4, A3, B5, C7),(X2, Y4, A5, B2, C3), (X2, Y4, A5, B2, C5), (X2, Y4, A3, B2, C6), (X2,Y4, A5, B3, C3), (X2, Y4, A5, B3, C5), (X2, Y4, A5, B3, C6), (X2, Y4,A5, B5, C3), (X2, Y4, A5, B35, C5), (X2, Y4, A5, B6, C5), (X2, Y4, A5,B7, C5), (X2, Y4, A5, B5, C6), (X2, Y4, A5, B5, C7), (X2, Y4, A7, B2,C3), (X2, Y4, A7, B2, C5), (X2, Y4, A7, B2, C6), (X2, Y4, A7, B3, C3),(X2, Y4, A7, B3, C5), (X2, Y4, A7, B3, C6), (X2, Y4, A7, B5, C3), (X2,Y4, A7, B5, C5), (X2, Y4, A7, B6, C5), (X2, Y4, A7, B7, C5), (X2, Y4,A7, B5, C6), (X2, Y4, A7, B5, C7), (X3, Y3, A3, B2, C3), (X3, Y3, A3,B2, C5), (X3, Y3, A3, B2, C6), (X3, Y3, A3, B3, C3), (X3, Y3, A3, B3,C5), (X3, Y3, A3, B3, C6), (X3, Y3, A3, B5, C3), (X3, Y3, A3, B5, C5),(X3, Y3, A3, B3, C5), (X3, Y3, A3, B7, C5), (X3, Y3, A3, B5, C6), (X3,Y3, A3, B5, C7), (X3, Y3, A5, B2, C3), (X3, Y3, A5, B2, C5), (X3, Y3,A5, B2, C6), (X3, Y3, A5, B3, C3), (X3, Y3, A5, B3, C5), (X3, Y3, A5,B3, C6), (X3, Y3, A5, B5, C3), (X3, Y3, A5, B5, C5), (X3, Y3, A5, B6,C5), (X3, Y3, A5, B7, C5), (X3, Y3, A5, B5, C6), (X3, Y3, A5, B5, C7),(X3, Y3, A7, B2, C3), (X3, Y3, A7, B2, C5), (X3, Y3, A7, B2, C6), (X3,Y3, A7, B3, C3), (X3, Y3, A7, B3, C5), (X3, Y3, A7, B3, C6), (X3, Y3,A7, B5, C3), (X3, Y3, A7, B5, C5), (X3, Y3, A7, B6, C5), (X3, Y3, A7,B7, C5), (X3, Y3, A7, B5, C6), (X3, Y3, A7, B5, C7), (X3, Y4, A3, B2,C3), (X3, Y4, A3, B2, C6), (X3, Y4, A3, B2, C6), (X3, Y4, A3, B3, C3),(X3, Y4, A3, B3, C5), (X3, Y4, A3, B3, C6), (X3, Y4, A3, B5, C3), (X3,Y4, A3, B5, C5), (X3, Y4, A3, B6, C5), (X3, Y4, A3, B7, C5), (X3, Y4,A3, B5, C6), (X3, Y4, A3, B5, C7), (X3, Y4, A5, B2, C3), (X3, Y4, A5,B2, C5), (X3, Y4, A5, B2, C6), (X3, Y4, A5, B3, C3), (X3, Y4, A5, B3,C5), (X3, Y4, A5, B3, C6), (X3, Y4, A5, B5, C3), (X3, Y4, A5, B5, C5),(X3, Y4, A5, B6, C5), (X3, Y4, A5, B7, C5), (X3, Y4, A5, B5, C6), (X3,Y4, A5, B5, C7), (X3, Y4, A7, B2, C3), (X3, Y4, A7, B2, C5), (X3, Y4,A7, B2, C6), (X3, Y4, A7, B3, C3), (X3, Y4, A7, B3, C5), (X3, Y4, A7,B3, C6), (X3, Y4, A7, B5, C3), (X3, Y4, A7, B5, C5), (X3, Y4, A7, B6,C5), (X3, Y4, A7, B7, C5), (X3, Y4, A7, B5, C6), (X3, Y4, A7, B5, C7),(X4, Y3, A3, B2, C3), (X4, Y3, A3, B2, C5), (X4, Y3, A3, B2, C6), (X4,Y3, A3, B3, C3), (X4, Y3, A3, B3, C5), (X4, Y3, A3, B3, C6), (X4, Y3,A3, B5, C3), (X4, Y3, A3, B5, C5), (X4, Y3, A3, B6, C5), (X4, Y3, A3,B7, C5), (X4, Y3, A3, B5, C6), (X4, Y3, A3, B5, C7), (X4, Y3, A5, B2,C3), (X4, Y3, A5, B2, C5), (X4, Y3, A5, B2, C6), (X4, Y3, A5, B3, C3),(X4, Y3, A5, B3, C5), (X4, Y3, A5, B3, C6), (X4, Y3, A5, B5, C3), (X4,Y3, A5, B5, C5), (X4, Y3, A5, B6, C5), (X4, Y3, A5, B7, C5), (X4, Y3,A5, B5, C6), (X4, Y3, A5, B5, C7), (X4, Y3, A7, B2, C3), (X4, Y3, A7,B2, C5), (X4, Y3, A7, B2, C6), (X4, Y3, A7, B3, C3), (X4, Y3, A7, B3,C5), (X4, Y3, A7, B3, C6), (X4, Y3, A7, B5, C3), (X4, Y3, A7, B5, C5),(X4, Y3, A7, B6, C5), (X4, Y3, A7, B7, C5), (X4, Y3, A7, B5, C6), (X4,Y3, A7, B5, C7), (X4, Y4, A3, B2, C3), (X4, Y4, A3, B2, C5), (X4, Y4,A3, B2, C6), (X4, Y4, A3, B3, C3), (X4, Y4, A3, B3, C5), (X4, Y4, A3,B3, C6), (X4, Y4, A3, B5, C3), (X4, Y4, A3, B5, C5), (X4, Y4, A3, B6,C5), (X4, Y4, A3, B7, C5), (X4, Y4, A3, B5, C6), (X4, Y4, A3, B5, C7),(X4, Y4, A5, B2, C3), (X4, Y4, A5, B2, C5), (X4, Y4, A5, B2, C6), (X4,Y4, A5, B3, C3), (X4, Y4, A5, B3, C5), (X4, Y4, A5, B3, C6), (X4, Y4,A5, B5, C3), (X4, Y4, A5, B5, C5), (X4, Y4, A5, B6, C5), (X4, Y4, A5,B7, C5), (X4, Y4, A5, B5, C6), (X4, Y4, A5, B5, C7), (X4, Y4, A7, B2,C3), (X4, Y4, A7, B2, C5), (X4, Y4, A7, B2, C6), (X4, Y4, A7, B3, C3),(X4, Y4, A7, B3, C5), (X4, Y4, A7, B3, C6), (X4, Y4, A7, B5, C3), (X4,Y4, A7, B5, C5), (X4, Y4, A7, B6, C5) (X4, Y4, A7, B7, C5), (X4, Y4, A7,B5, C6), (X4, Y4, A7, B5, C7), (X5, Y5, A3, B2, C3), (X5, Y5, A3, B2,C5), (X5, Y5, A3, B2, C6), (X5, Y5, A3, B2, C7), (X5, Y5, A3, B2, C8),(X5, Y5, A3, B3, C3), (X5, Y5, A3, B3, C5), (X5, Y5, A3, B3, C6), (X5,Y5, A3, B3, C7), (X5, Y5, A3, B3, C8), (X5, Y5, A3, B5, C3), (X5, Y5,A3, B5, C5), (X5, Y5, A3, B5, C6), (X5, Y5, A3, B5, C7), (X5, Y5, A3,B5, C8), (X5, Y5, A3, B6, C3), (X5, Y5, A3, B6, C5), (X5, Y5, A3, B6,C6), (X5, Y5, A3, B6, C7), (X5, Y5, A3, B6, C8), (X5, Y5, A3, B7, C3),(X5, Y5, A3, B7, C5), (X5, Y5, A3, B7, C6), (X5, Y5, A3, B7, C7), (X5,Y5, A3, B7, C8), (X5, Y5, A3, B8, C3), (X5, Y5, A3, B8, C5), (X5, Y5,A3, B8, C6), (X5, Y5, A3, B8, C7), (X5, Y5, A3, B8, C8), (X5, Y5, A5,B2, C3), (X5, Y5, A5, B2, C5), (X5, Y5, A5, B2, C6), (X5, Y5, A5, B2,C7), (X5, Y5, A5, B2, C8), (X5, Y5, A5, B3, C3), (X5, Y5, A5, B3, C5),(X5, Y5, A5, B3, C6), (X5, Y5, A5, B3, C7), (X5, Y5, A5, B3, C8), (X5,Y5, A5, B5, C3), (X5, Y5, A5, B5, C5), (X5, Y5, A5, B5, C6), (X5, Y5,A5, B5, C7), (X5, Y5, A5, B5, C8), (X5, Y5, A5, B6, C3), (X5, Y5, A5,B6, C5), (X5, Y5, A5, B6, C6), (X5, Y5, A5, B6, C7), (X5, Y5, A5, B6,C8), (X5, Y5, A5, B7, C3), (X5, Y5, A5, B7, C5), (X5, Y5, A5, B7, C6),(X5, Y5, A5, B7, C7), (X5, Y5, A5, B7, C8), (X5, Y5, A5, B8, C3), (X5,Y5, A5, B8, C5), (X5, Y5, A5, B8, C6), (X5, Y5, A5, B8, C7), (X5, Y5,A5, B8, C8), (X5, Y5, A7, B2, C3), (X5, Y5, A7, B2, C5), (X5, Y5, A7,B2, C6), (X5, Y5, A7, B2, C7), (X5, Y5, A7, B2, C8), (X5, Y5, A7, B3,C3), (X5, Y5, A7, B3, C5), (X5, Y5, A7, B3, C6), (X5, Y5, A7, B3, C7),(X5, Y5, A7, B3, C8), (X5, Y5, A7, B5, C3), (X5, Y5, A7, B5, C5), (X5,Y5, A7, B5, C6), (X5, Y5, A7, B5, C7), (X5, Y5, A7, B5, C8), (X5, Y5,A7, B6, C3), (X5, Y5, A7, B6, C5), (X5, Y5, A7, B6, C6), (X5, Y5, A7,B6, C7), (X5, Y5, A7, B6, C8), (X5, Y5, A7, B7, C3), (X5, Y5, A7, B7,C5), (X5, Y5, A7, B7, C6), (X5, Y5, A7, B7, C7), (X5, Y5, A7, B7, C8),(X5, Y5, A7, B8, C3), (X5, Y5, A7, B8, C5), (X5, Y5, A7, B8, C6), (X5,Y5, A7, B8, C7), (X5, Y5, A7, B8, C8), (X5, Y5, A8, B2, C3), (X5, Y5,A8, B2, C5), (X5, Y5, A8, B2, C6), (X5, Y5, A8, B2, C7), (X5, Y5, A8,B2, C8), (X5, Y5, A8, B3, C3), (X5, Y5, A8, B3, C5), (X5, Y5, A8, B3,C6), (X5, Y5, A8, B3, C7), (X5, Y5, A8, B3, C8), (X5, Y5, A8, B5, C3),(X5, Y5, A8, B5, C5), (X5, Y5, A8, B5, C6), (X5, Y5, A8, B5, C7), (X5,Y5, A8, B5, C8), (X5, Y5, A8, B6, C3), (X5, Y5, A8, B6, C5), (X5, Y5,A8, B6, C6), (X5, Y5, A8, B6, C7), (X5, Y5, A8, B6, C8), (X5, Y5, A8,B7, C3), (X5, Y5, A8, B7, C5), (X5, Y5, A8, B7, C6), (X5, Y5, A8, B7,C7), (X5, Y5, A8, B7, C8), (X5, Y5, A8, B8, C3), (X5, Y5, A8, B8, C5),(X5, Y5, A8, B8, C6), (X5, Y5, A8, B8, C7) or (X5, Y5, A8, B8, C8).

A method of preparing a compound (I) will be explained below.

(Method of Preparing Compound (I))

A compound (I) can be synthesized by α-haloalkoxycarbonizing —NH— of acompound represented by the formula (IV)(hereinafter, referred to as acompound (IV)):

wherein one of X and X′ is —NH—, the other is —(CH₂)s- (wherein s is aninteger of 0 to 2), —O, —NR^(A)— (wherein R^(A) is hydrogen, optionallysubstituted lower alkyl, lower alkenyl or lower alkylcarbonyl) or—S(O)P— (wherein p is an integer of 0 to 2), and other symbols have thesame meanings as those described above and, thereafter, reacting thecarbonized compound with a suitable carboxylic acid under the suitableconditions. Such the method of synthesizing acyloxyalkyl carbamate maybe carried out by a method described in WO96/18605 and the like.

(In the Case of Compound (IV) Wherein X═NH)

(Wherein Respective Symbols Have the Same Meanings as Those DescribedAbove)

More specifically, a compound (IV) is reacted with chloroformicα-haloalkyl ester in an inert solvent such as diethyl ether,tetrahydrofuran, 1,4-dioxane, ethyl acetate or toluene in the presenceof a base such as triethylamine or N-methylmorpholine at 0° C. to roomtemperature to obtain an intermediate compound represented by the aboveformula (V) (hereinafter, referred to as a compound (V)) quantitatively.

Then, the compound (V) is reacted with a salt (such as alkali metalsalt, alkaline earth metal salt, silver salt, mercury salt or the like)of a carboxylic acid compound having a substituent R¹ of interest in asolvent such as N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide, sulfolane or the like at room temperature to underheating for hours to for days to obtain a compound (I). Alternatively, afree carboxylic acid may be used in the presence of an alkali metalsalt, an alkaline earth metal salt, silver salt or the like of carbonateor bicarbonate to obtain a target compound. The present reaction can becarried out in the presence of KBr or NaI to substitute C1 of a compound(V) with more reactive Br or I.

Also in the case of a compound (IV) wherein X′ is —NH—, a targetcompound can be obtained as described above. In addition, in the casewherein X and X′ are both —NH—, a compound wherein X and/or X′ is (are)modified for a prodrug can be obtained by adjusting an amount ofchloroformic a-haloalkyl ester to be added.

A compound (IV) which is a secondary amine can be converted into acompound (I) also by a method using para-nitrophenyl acyloxyalkylcarbonate (P-NO₂C₆H₄OCOOC(R^(A)) (R^(B))OCOR¹) described in U.S. Pat.No. 4,760,057.

Furthermore, as a method of synthesizing a compound (I), there is knowna method using acyloxyalkyl carbochloridate (R¹COOC(R^(A))(R^(B))OCOCl)described in JP-A18747/1986.

A compound (IV) used in the above reaction can be synthesized by amethod described in WO97/39999, or WO98/04508 or the following method.

(Method of Preparing Compound (IV′))

A compound represented by the following formula (IV′) (hereinafter,referred to as a compound (IV′)) can be prepared by reacting a compoundrepresented by the formula (VIa) (hereinafter, referred to as a compound(VIa)) with a bicyclic compound represented by the formula (VIIa)(hereinafter, referred to as a compound (VIIa)), or reacting a compoundrepresented by the formula (VIb) (hereinafter, referred to as a compound(VIb)) with a bicyclic compound represented by the formula (VIIb)(hereinafter, referred to as a compound (VIIb))

wherein one of L and Z is dihydroxyboryl, di-lower alkylboryl ordi-lower alkoxyboryl, the other is halogen or —OSO₂(C_(q)F_(2q+1)) (q isan integer of 0 to 4), and other symbols have the same meanings as thosedescribed above.

A compound (VIa) and a compound (VIIa) or a compound (VIb) and acompound (VIIb) are reacted in a mixed system of a suitable solvent(such as benzene, toluene, N,N-dimethylformamide, dimethoxyethane,tetrahydrofuran, dioxane, ethanol or methanol) and water or anon-aqueous system in the presence of a palladium catalyst (such asPd(PPh₃)₄, PdCl₂(PPh₃)₂, PdCl₂(OAc)₂ and PdCl₂(CH₃CN)₂, preferablyPd(PPh₃)₄) under the basic conditions (examples of the base are K₃PO₄,NaHCO₃, NaOEt, Na₂CO₃, Et₄NCl, Ba(OH)₂, Cs₂CO₃, CsF, NaOH and Ag₂CO₃) atroom temperature to under heating for tens minutes to tens hours toobtain a compound (IV′).

One of substituents L and Z in compounds to be reacted with each othermay be any boryl group as far as it can be applied to a Suzuki reaction(Chemical Communication 1979, 866, Journal of Synthetic OrganicChemistry, Japan, 1993, vol. 51, No. 11, p91-100). Preferably, it isdihydroxyboryl. The other is any leaving group as far as it can beapplied to a Suzuki reaction. For example, halogen or—OSO₂(C_(q)F_(2q+1)) (wherein q is an integer of 0 to 4) can be used. Inparticular, halogen and trifluoromethanesulfonyloxy (hereinafter,referred to as OTf) are preferable, and bromine, iodine and OTf are mostpreferable.

As other substituents, —X—Y and —X′—Y′ for ring A, ring B and ring C ofcompounds (VIa), (VIIa), (VIb) and (VIIb), groups having no adverseinfluence on a Suzuki reaction, for example, groups other than halogenand —OSO₂(C_(q)F_(2q+2)) (wherein q is an integer of 0 to 4) arepreferable.

For example, Y and Y′ may be optionally substituted lower alkyl,optionally substituted lower alkenyl, optionally substituted loweralkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkenyl, optionally substituted aryl or optionally substituted5-membered or 6-membered heterocycle. In addition, when X is —CH₂—, Ymay be optionally substituted lower alkoxy and, when X′ is —CH₂—, Y′ maybe optionally substituted lower alkoxy. In addition, when X is —O— or—NR^(A)—, Y may be optionally substituted lower alkoxycarbonyl,optionally substituted lower alkylsulfonyl or optionally substitutedarylsulfonyl and, when X′ is —O— or —NR^(A)—, Y′ may be optionallysubstituted lower alkoxycarbonyl, optionally substituted loweralkylsulfonyl or optionally substituted arylsulfonyl.

Even when any substituent of ring A, ring B and ring C is halogen, ifthe reactivity between a substituent L and a substituent Z is higherthan that of halogen with either of substituents L and Z, the presentreaction can proceed without any problem.

Even when any substituent —X—Y or —X′—Y′ of ring A, ring B, ring C ishydroxy, the above reaction can be performed. In such the case,preferably, after protected with a hydroxy protecting group normallyused (such as methoxymethyl, benzyl, t-butyldimethylsilyl,methanesulfonyl and p-toluenesulfonyl), the substituent is subjected tothe above reaction and, thereafter, a normal deprotecting reaction isperformed. Although as a method of synthesizing a compound (IV′), it ispreferable to utilize the above Suzuki reaction for the best efficiencyand more simplicity, a reaction may be performed using silicon, zinc,tin or the like in place of a boryl group in the above scheme.

For example, when one of A and Z is —SiR^(D) _(3-r)(Hal)_(r) (whereinR^(D) may be each different and is lower alkyl, Hal is halogen, and r isan integer of 1 to 3), and the other is halogen or —OSO₂(C_(q)F_(2q+1))(wherein q is an integer of 0 to 4), a coupling reaction is performedusing a normally used palladium catalyst (Synlett (1991) 845-853, J.Org. Chem. 1996, 61, 7232-7233). Examples of a preferable palladiumcatalyst include (i-Pr₃P)₂PdCl₂,[(dcpe)PdCl₂](dcpe=1,2-bis(dicyclohexylphosphino)ethane and(η³—C₃H₅PdCl)₂.

In addition, even when one of L and Z is —SnR^(E) ₃ (wherein R^(E) maybe each different and is lower alkyl) and the other is halogen,acetyloxy or —OSO₂(C_(q)F_(2q+1))(wherein q is an integer of 0 to 4), atarget compound can be obtained using a normally used palladium catalyst(preferably, Pd(PPh₃)₄ and the like) (Angew. Chem. Int. Ed. Engl. 25(1986) 508-524).

Even when a compound wherein one of L and Z is —Zn(Hal) (wherein Hal ishalogen) and the other is halogen is reacted, a target compound can besynthesized (Acc. Chem. Res. 1982, 15, 340-348). Any palladium catalystcan be used as far as they are generally used. Preferable examplesinclude Pd(PPh₃)₄, PdCl₂(dppf) (dppf=1,1′-bis (diphenylphosphino)ferrocene), PdCl₂(PPh₃)₂, PdCl₂(P(o-Tolyl)₃)₂ and Pd(OAc)₂.

These reactions may be performed in a suitable solvent (such asN,N-dimethylformamide, tetrahydrofuran and the like) at room temperatureto under heating for tens minutes to tens hours.

(Method of Preparing Compounds (VIIa) and (VIIb))

As the compounds (VIIa) and (VIIb) in the above reaction formula, theknown compounds may be used, or compounds derived from a compoundrepresented by the following formula (IXa) (hereinafter, referred to asa compound (IXa)) or a compound represented by the following formula(IXb) (hereinafter, referred to as a compound (IXb)) which issynthesized by the known method or the following method may be used:

wherein D is a group having no influence on a Suzuki reaction of L and Zand, when a compound represented by the formula (VIIIa) or the formula(VIIIb) is a symmetric compound, it may be the same group as L, andother symbols have the same meanings as those described above.

First, a compound (VIb) and a compound (VIIIa) or a compound (VIa) and acompound (VIIIb) are reacted as in the above step to obtain a compound(IXa) or (IXb). When a compound (VIIIa) or (VIIIb) is not a symmetriccompound, D is preferably a group which has no adverse influence on aSuzuki reaction of L and Z and can be simply derived into L. Examples ofD include hydroxy, hydrogen, formyl and nitro. In L and Z, a reactioncan be performed using silicon, zinc or tin in place of a boryl group asdescribed above.

Then, D is converted into a substituent L which is applicable to aSuzuki reaction.

For example, when D is hydroxy, D is reacted with atrifluoromethanesulfonylating agent (such as trifluoromethanesulfonicanhydride, trifluoromethanesulfonyl chloride andN-phenyltrifluoromethanesulfonimide) in a suitable solvent (such asdichloromethane, chloroform, tetrahydrofuran, benzene and toluene) inthe presence of a base (such as sodium hydride, pyridine, triethylamineand potassium carbonate) at −20° C. to under heating for tens minutes totens hours to obtain a target compound wherein L is OTf.

In addition, when D is hydrogen, it is reacted with a halogenating agent(such as chlorine, bromine, iodine and N-bromosuccinic imide) in asuitable solvent (such as acetic acid, dichloromethane, chloroform,carbon tetrachloride, N,N-dimethylformamide and water) at −20° C. tounder heating for tens minutes to tens hours to obtain a target compoundwherein L is halogen.

When D is formyl, it is Baeyer-Villiger-oxidized to formyloxy by anormal method, which is further hydrolyzed to hydroxy. Thereafter, thesame procedures as those described above can afford a compound wherein Lis OTf.

When D is nitro, it may be reduced to amino which is subjected to aSandmeyer reaction to obtain a compound wherein L is halogen.

Among a compound (VIIb), a compound represented by the following formula(VIIb′);

wherein one of R⁴ and R⁵ is hydrogen and the other is halogen, R⁸ andR¹⁰ are each independently hydrogen, hydroxy or lower alkyl, R⁹and R¹⁰are each independently lower alkyl, lower alkoxy or loweralkoxycarbonyl, L′ is dihydroxyboryl, di-lower alkylboryl or di-loweralkoxyboryl, is particularly preferable. Most preferable L′ isdihydroxyboryl. By using this intermediate, it can be directly subjectedto a Suzuki reaction to synthesize a target compound (IV′) withouttroublesome protection and deprotection reaction.

This compound (VIIb′) can be also synthesized by the following method:

wherein respective symbols have the same meanings as those describedabove.

First, the known compound (IXc) or a compound (IXc) obtained by a normalmethod and 3-methyl-2-butenal are reacted with a reducing agent such assodium borohydride, sodium cyanotrihydroborohydride, sodiumtriacetoxyborohydride, sodium trimethoxyborohydride anddiisopropoxyboron chloride in a suitable solvent such asdichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane,dioxane, toluene or benzene in the presence of a neutral to acidiccompound, preferably an acidic compound such as acetic acid at 0C tounder heating for tens minutes to tens hours to obtain a compound (IXd).The resulting compound is reacted with n-butyllithium, sec-butyllithium,phenyllithium or the like in a suitable solvent such as tetrahydrofuran,diethylether, dimethoxyethane or the like at −100° C. to roomtemperature to obtain a lithium salt which can be reacted with a borateester such as triisopropyl borate, trimethyl borate, tributyl borate orthe like to obtain a compound (VIIb′).

(Method of Preparing Compound (IV″))

A compound represented by the following formula (IV″)(hereinafter,referred to as a compound (IV″)) can be prepared by a Suzuki reaction ofa compound represented by the formula (X) (hereinafter, referred to as acompound (X)) and a compound represented by the formula (VIa)(hereinafter, referred to as a compound (VIa)) or condensation of acompound represented by the formula (XI) (hereinafter, referred to as acompound (XI)) and a compound represented by the formula (XII)(hereinafter, referred to as a compound (XII))

wherein one of M and Q is hydroxy or amino and the other is halogen,lower alkylsulfonyloxy, arylsulfonyloxy, lower alkylsulfonyl orarylsulfonyl or methyl having these as a substituent, or one of them islithium or Mg(Hal) (wherein Hal is halogen) and the other is carboxy,lower alkoxycarbonyl, carbamoyl or formyl, or one of them is formyl andthe other is halomethyl, or one of them is ethynyl and the other ishalogen, and other symbols have the same meanings as those describedabove.

The various conditions in a reaction of a compound (X) and a compound(VIa) are the same as those for preparation of the compound (IV′).

In a reaction of a compound (XI) and a compound (XII), when V² in atarget compound is —O—, —NH—, —OCH₂—, —CH₂O— or —NHCH₂—, one ofsubstituents M and Q is hydroxy or amino, and the other is a leavinggroup such as halogen, lower alkylsulfonyloxy, arylsulfonyloxy, loweralkylsulfonyl and arylsulfonyl or methyl having these leaving groups asa substituent. These two compounds are reacted in a suitable solvent(such as benzene, toluene, acetone, acetonitrile, N,N-dimethylformamide,dimethyl sulfoxide, pyridine, methanol and ethanol) in the presence of abase (such as sodium hydride, pyridine, triethylamine, potassiumcarbonate, sodium hydroxide and potassium hydroxide) and, if necessary,by adding a copper catalyst (such as copper powder, CuCl and CuO) at 0°C. to under heating for tens minutes to tens hours to obtain a targetcompound.

In a reaction of a compound (XI) and a compound (XII), when V² in atarget compound is —CO— or —CH(OH)—, one of substituents M and Q is anorganic metal such as lithium or Mg(Hal)(wherein Hal is halogen), andthe other is carboxy, lower alkoxycarbonyl, carbamoyl or formyl. Thesetwo compounds are reacted in a suitable solvent (such as diethyl ether,tetrahydrofuran, dimethoxyethane and dioxane) at −78° C. to underheating for tens minutes to tens hours to obtain a target compound.

When V² for a target compound is —CH(OH)— (wherein R is lower alkyl), acompound wherein V² is —CH(OH)— is first obtained, which may be thenalkylated.

In addition, a compound wherein V² for a target compound is —CO— may bealso obtained by reacting a compound wherein V² is —CH(OH)— using anoxidizing agent such as chromic anhydride and a Jones regent in asolvent such as t-butyl alcohol and acetone at 0° C. to under heatingfor hours. A compound wherein V² for a target compound is —CH(OH)— maybe also prepared by reducing a compound wherein V² is —CO— with sodiumborohydride or aluminium lithium hydride in a suitable solvent (such asdiethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, methanol andethanol).

When V²for a target compound is —CH═CH—, one of substituents M and Q isformyl and the other is halomethyl (wherein the halogen is, for example,chlorine, bromine or iodine). In this case, a target compound can beobtained by a Wittig reaction (Organic Reaction, 1965, VOL.14, p270).

When V² for a target compound is —CH≡CH—, one of substituents M and Q isethynyl and the other is halogen (preferably, bromine or iodine). Atarget compound can be synthesized by performing a coupling reactionusing a normally used palladium catalyst (Synthesis (1980) 627,Tetrahedron, 1982, 38, 631).

Other substituents, —X—Y— and —X′—Y′ for ring A, ring B and ring C incompounds (X), (VIa), (XI) and (XII) may be any group as far as theyhave no adverse influence on a Suzuki reaction of L and Z or acondensation reaction of M and Q. However, even when any substituent ishalogen in a reaction of a compound (X) and a compound (VIa), if thereactivity of a substituent L and a substituent Z is higher than that ofhalogen with either of substituents L and Z, the present reaction canproceed without any problem. Even when any substituent is hydroxy, theabove reaction can proceed. In such the case, hydroxy is preferablyprotected in advance and, after subjected to the above reaction, anormal deprotection reaction is performed.

As a compound (X) in the above reaction formula, the known compound maybe used, or a compound synthesized by using a compound represented bythe formula (XIV) (hereinafter, referred to as a compound (XIV)) by theknown method or the following method may be used:

wherein D′ is a group having no adverse influence on a condensationreaction of Mand Q and, when, a compound represented by the formula(XIII) is a symmetric compound, D′ may be the same group as Q, and othersymbols have the same meanings as those described above.

When a compound (XIII) is not a symmetric compound, more specifically,D′ is preferably a group which has no adverse influence on acondensation reaction of M and Q and can be simply derived into L.Examples thereof include hydrogen, formyl, and protected hydroxy andnitro. Examples of a group for protecting hydroxy include benzyl,t-butyldimethylsilyl and methoxymethyl. A method of converting D′ into Lis the same for conversion of D into L. Other various conditions are thesame as those for a reaction of a compound (XI) and a compound (XII).

(Method of Preparing Compound (IV′″))

A compound represented by the formula (IV′″):

wherein respective symbols have the same meanings as those describedabove, can be synthesized as in the above compound (IV″).

(Method of Preparing Compound (IV) (Alternative Method))

As an alternative method of synthesizing a compound (IV), a targetcompound (IV) can be obtained by first constructing a tricyclicstructure and, thereafter, introducing a side chain —X′—Y′. An exampleof a compound (IV′) will be explained below:

wherein T is NH₂, or a group which has no adverse influence on a Suzukireaction and can be converted into U by a normal method (such asoptionally protected hydroxy, lower alkylthio and arylthio), U is aleaving group (such as halogen, lower alkylsulfonyl, arylsulfonyl, loweralkylsulfonyloxy and arylsulfonyloxy), s is an integer of 0 to 2, andother symbols have the same meanings as those described above.

First, a compound represented by the formula (VIIa′) (hereinafter,referred to as a compound (VIIa′)) and a compound (VIa), or a compound(VIIb) and a compound represented by the formula (VIb′) (hereinafter,referred to as a compound (VIb′)) are reacted by the aforementionedSuzuki reaction to obtain a compound (IV′″). The present reaction may beperformed as in the aforementioned reaction of a compound (VIa) and acompound (VIIa) or a compound (VIb) and a compound (VIIb).

Then, T of the resulting compound (IV′″) is converted into U accordingto the conventional method.

For example, when T is hydroxy, it can be converted into halogen underthe normal conditions, or a sulfonyl compound can be obtained by using asuitable sulfonating agent (such as methanesulfonyl chloride,p-toluenesulfonyl chloride and trifluoromethanesulfonic anhydride). WhenT is hydroxy which has been protected with a protecting group such asbenzyl, t-butyldimethylsilyl and methoxymethyl in advance, the protectedgroup is deprotected to hydroxy by a normal method and, thereafter, theaforementioned procedures can afford a target compound.

In addition, when T is lower alkylthio or optionally substitutedarylthio, it may be converted into a corresponding sulfonyl compoundusing a suitable oxidizing agent (such as hydrogen peroxide, peraceticacid, m-chloroperbenzoic acid and OXON (monopersulfate compound).

Then, a compound (IV″) is subjected to a substitution reaction to obtaina compound (IV′). For example, an alcohol (Y′—OH) or an amine(Y′—NHR^(A)) and a compound wherein S=0 are reacted in a suitablesolvent such as tetrahydrofuran, N,N-dimethylformamide, dioxane anddiethyl ether in the presence of a base such as sodium hydride, sodiummethylate and sodium bentoxide at room temperature to under heating fortens minutes to tens hours to obtain a compound (IV′) wherein X′ is O orNR^(A). In addition, in order to obtain a compound (IV′) wherein X is(CH₂)s, a nucleophilic compound having a substituent Y′ of interest anda compound (IV″) wherein s=1 or 2 may be reacted under similarconditions.

(Method of Preparing Compound (VIb′)]

A compound represented by the formula (VIb′) (hereinafter, referred toas a compound (VIb′)) in the above scheme can be synthesized, forexample, by the following method. 1) In the case where Z=halogen,dihydroxyboryl, di-lower alkylboryl or di-lower alkoxyboryl

wherein Hal¹ and Hal² are halogen, Z′ is dihydroxyboryl, di-loweralkylboryl or di-lower alkoxyboryl, and other symbols have the samemeanings as those described above.

First, the known compound or a compound represented by the formula(VIb″) (hereinafter, referred to as a compound (VIb′)) obtained by theconventional method is subjected to a normal substitution reaction toobtain compound (VIb′:Z=halogen). The thus obtained compound can bereacted with a boric ester such as triisopropyl borate, trimethylborate, tributyl borate and diisopropoxyboran chloride in a solvent suchas tetrahydrofuran, dioxane and hexane in the presence of a base such asn-butyllithium and sec-butyllithium to obtain a compound (VIb′:Z═Z′).

2) In the case where Z is OSO₂(C_(q)F_(2q+1))

A compound (VIb′:Z═OSO₂(C_(q)F_(2q+1))) is obtained by reacting theknown compound or a compound (VIb′″)obtained by the known method withfluoroalkanesulfonic acid such as trifluoromethanesulfonic anhydride ina solvent such as dichloromethane in the presence of a base such aspyridine.

Among the above compound (VIb′), in particular, a compound wherein ringC is pyridine ring optionally substituted with lower alkyl or pyrimidinering optionally substituted with lower alkyl, T is protected hydroxy,lower alkylthio or arylthio and Z′ is dihydroxyboryl, di-loweralkylboryl or di-lower alkoxyboryl is preferable as an intermediate fora compound (IV) and a compound (I). A more preferable compound is acompound wherein T is lower alkylthio or phenylthio, Z′ isdihydroxyboryl and s is 0.

Hitherto, since pyridineboronic acid has the too high water-solubility,it has been very difficult to synthesize (particularly, isolation andpurification). However, by introducing a substituent T—(CH₂)s-,synthesis has become easy, allowing it to be prepared at a higher yield.In addition, when T is converted into a leaving group, it is possible tosubstitution-react with various nucleophilic regents, leading a usefulintermediate for synthesizing medicines, agricultural chemicals andliquid crystal compounds having the 2,5-di-substituted pyridine andpyrimidine skeleton as a partial structure.

Regarding compounds having a substituent interfering with the abovereaction, the group may be protected with a suitable protecting group inadvance, and the protected group may be deprotected by the conventionalmethod at a suitable stage. For example, when hydroxy interferes withthe reaction, it may be protected with a protecting group such asmethoxymethyl, methanesulfonyl, benzyl, trifluoromethanesulfonyl ort-butyldimethylsilyl and, when amino interferes with the reaction, itmay be protected with a protecting group such as lower alkoxycarbonyl,lower alkenyloxycarbonyl, halogenoalkoxycarbonyl or aralkyloxycarbonyl,and the suitable protecting group may be eliminated at a suitable stage.

For example, when hydroxy is protected with methanesulfonyl, hydroxy maybe reacted with methanesulfonyl chloride in a solvent such asdichloromethane, chloroform or carbon tetrachloride in the presence of abase such as triethylamine or pyridine at under ice-cooling to roomtemperature for several hours. When the protected hydroxy is subjectedto a deprotection reaction, it may be reacted by adding 1 to 4 N sodiumhydroxide, potassium hydroxide, an aqueous solution thereof, sodiummethoxide or ethylmagnesium bromide in a solvent such asdimethylsulfoxide, N,N-dimethylformamide, tetrahydrofuran, dioxane anddimethoxyethane at room temperature to under heating for tens minutes totens hours.

When methoxymethyl is used as a group for protecting hydroxy, hydroxycan be reacted with chloromethyl=methyl=ether in a solvent such astetrahydrofuran, dioxane and dimethoxyethane in the presence of sodiumhydride, diisopropylethylamine to obtain protected hydroxy. When theprotected hydroxy is deprotected, a normal deprotection reaction may becarried out using hydrochloric acid or sulfuric acid in a solvent suchas methanol, tetrahydrofuran and acetic acid.

When t-butyldimethylsilyl is used as a protecting group, hydroxy may bereacted with t-butyldimethylsilyl chloride ort-butyldimethylsilyltriflate in a solvent such as N,N-dimethylformamide,acetonitrile, tetrahydrofuran and dichloromethane in the presence ofimidazole, triethylamine or 2,6-lutidine. When a deprotection reactionis performed by reacting with tetrabutylammonium fluoride in a solventsuch as tetrahydrofuran, a protecting group can be eliminated.

A compound (I) is degraded in the living body and can be converted intoa compound (IV) which is an active form. Since a compound (I) shows theextremely good oral absorbability under non-fasting or fasting ascompared with a compound (IV), the high pharmacological effects can beobtained and, thus, the compound (I) is useful as a prodrug. Inaddition, the compound (I) has physical advantages that it has a highmelting point and it does not generate static electricity and, thus, itcan be simply formulated into preparations.

A compound (IV) inhibits the mitogen reaction and/or cytokine reaction,and shows the strong immunosuppressive activity and antiallergicactivity. More specifically, the active compound has the very stronggrowth inhibiting activity against both T and B cells, and/or theantibody production inhibiting activity against IgE, IgG and the like.Accordingly, the present compound can be administered as a medicine forinhibiting immunoreaction or treating or preventing allergic diseases inan animal including human being.

An immunosuppressive agent or an antiallergic agent containing thepresent compound is useful for preventing or treating an rejectionreaction against organs or tissues transplantation and agraft-versus-host reaction caused by bone marrow transplantation as wellas allergic diseases such as rheumatoid arthritis, systemic lupuserythematosus, asthma, inflammatory colitis, injury inischemia-reperfusion, allergic rhinitis, allergic conjunctivitis, atopy,urticaria and psorias is.

When an immunosuppressive agent and/or an antiallergic agent containingthe present compound is administered, administration can be performed byorally or parenterally. Oral administration may be performed bypreparing into normally used dosage forms such as tablets, granules,powders, capsules, pills, solutions, syrups, buccals and sublingualtablets according to the conventional method. Parenteral administrationmay be suitably performed by any normally used dosage form such asinjections (intramuscular or intravenous), suppositories, percutaneousabsorption agents and inhalants. In particular, oral administration ispreferable.

If necessary, various medical additives such as excipients, binders,wetting agents, disintegrating agents, lubricants and diluents suitablefor the dosage form can be mixed with an appropriate amount of thepresent compound to obtain a pharmaceutical preparation. In the case ofinjections, the present compound may be sterilized with a suitablecarrier to obtain a preparation.

More specifically, excipients include lactose, sucrose, glucose, starch,calcium carbonate and crystalline cellulose, binders includemethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatinor polyvinylpyrrolidone, disintegrating agents includecarboxymethylcellulose, sodium carboxymethylcellulose, starch, sodiumalginate, agar powders and sodium lauryl sulfate, and lubricants includetalc, magnesium stearate and macrogol. As a base for suppositories,cocoa butter, macrogol and methylcellulose can be used. Furthermore,when prepared into solutions or emulsified or suspended injections,normally used solubilizers, suspending agents, emulsifiers, stabilizers,preservatives and isotonic agents may be appropriately added and, whenorally administered, sweetening agents and flavors may be added. A doseof an immunosuppressive agent and/or an antiallergic agent containingthe present compound is desirably set considering age and weight of apatient, the type and degree of diseases, and a route of administrationand, when orally administered to an adult, it is usually in a range of0.05 to 100 mg/kg/day, preferably 0.1 to 10 mg/kg/day. When parenterallyadministered, a dose varies remarkably depending upon a route ofadministration and is usually inarangeof 0.005 to 10 mg/kg/day,preferably 0.01 to 1 mg/kg/day. This may be administered by dividinginto once to a few times per day.

The present invention will be explained in more detail by the followingExamples but the present invention is not limited to them. Thestructural formulas of respective compounds in examples and referenceexamples are summarized in Table 1 to Table

EXAMPLES Reference Example 1 Synthesis of Compound II-1

(First Step)

An aqueous solution (150 mL) of boronic acid(2) (22.88 g, 0.1 mol) andsodium carbonate (31.8 g, 0.3 mol) was added to a solution of a compound(1) (23.7 g, 0.1 mol) in dimethoxyethane (300 mL)-ethanol(150 mL), andthe reaction solution was degassed. Tetrakis (triphenylphosphine)palladium (3.47 g, 3 mmol) was added, the mixture was heated at refluxfor 2 hours under a nitrogen atmosphere. After diluted with water, thereaction was extracted with ethyl acetate. The extract was washed with asaturated brine, dried, concentrated, and the resulting residue wascrystallized from hexane to obtain a compound (3) (24.92 g; yield 84% ).

(Second Step)

According to the same manner as that of the first step, a compound (3)(20.0 g, 68.0 mmol) and boronic acid (VIb′-1) (14.94 g, 88.3 mmol) werereacted for 18 hours, and the extract residue was purified by silica gelchromatography (hexane-ethyl acetate 2:1) to obtain a compound (4)(19.24 g; yield 84%).

(Third Step)

Pyridine (6.6 mL, 81.2 mmol) followed by trifluoroacetic anhydride (10.6mL, 75.0mmol) was added to a solution of acompound (4) (21.15 g, 62.5mmol) in dichloromethane (200 mL) under ice-cooling, and the mixture wasstirred at room temperature for 1 hour. The reaction solution wasdiluted with ethyl acetate. The organic layer was washed successivelywith water, 1N hydrochloric acid, a 5% aqueous sodium bicarbonatesolution and a saturated brine, dried, and concentrated to obtain acompound (5) (22.80 g; yield 84%).

(Fourth Step)

m-Chloroperbenzoic acid (14.46 g, 83.8 mmol) was added to a solution ofacompound (5) (14.0 g, 32.2 mmol) indichloromethane (300 mL) underice-cooling, and the mixture was stirred at room temperature for 3hours. After an aqueous solution of sodium thiosulfate was added to thereaction solution, the mixture was extracted with ethyl acetate. Theorganic layer was washed with an aqueous saturated sodium bicarbonatesolution twice, dried and concentrated. The residue was washed withhexane to obtain a compound (6) (12.97 g; yield 86%).

(Fifth Step)

Potassium carbonate (6.67 g, 48.2 mmol) followed by prenyl bromide (4.8mL, 41.8 mmol) was added to a solution of a compound (6) (15.0 g, 32.2mmol) in N,N-dimethylformamide (65 mL), and the mixture was stirred atroom temperature for 18 hours. The reaction solution was diluted withethyl acetate, washed successively with water and a saturated brine,dried, concentrated, and the residue was dissolved in tetrahydrofuran(150 mL). A reaction solution prepared by adding sodium hydride (60%mineral oil, 3.85 g, 96.5 mmol) to a solution of prenol (9.8 mL, 96.5mmol) in tetrahydrofuran (150 mL) was added under ice-cooling, and themixture was further stirred at the same temperature for 2 hours. Afterthe reaction mixture was diluted with ethyl acetate, the organic layerwas washed successively with water and a saturated brine, dried andconcentrated. The residue was purified by silica gel chromatography(hexane-ethyl acetate 7:1) to obtain a compound II-1 (12.5 g; yield87%).

Mp: 87-88° C.

¹H NMR (CDCl₃) δ H 1.74 (s, 3H), 1.78 (s, 3H), 1.79 (s, 3H), 1.80 (s,3H), 2.22 (s, 3H), 2.26 (s, 3H), 3.71 (d, J=6.9 Hz, 2H), 4.87 (d, J=7.2Hz, 2H), 5.32-5.37 (m, 1H), 5.55-5.60 (m, 1H), 6.35-6.47 (m, 2H), 6.81(dd, J=0.6, 8.4 Hz, 1H), 7.02-7.13 (m, 3H), 7.59 (dd, J=2.4, 8.4 Hz,1H), 8.16 (dd, J=0.9, 5.7 Hz, 1H).

IR (Nujol): 3330, 2923, 2853, 1627, 1606, 1564, 1527, 1481, 1471, 1395,1376, 1357, 1337, 1284, 1240, 1178, 1116, 990 cm⁻¹.

Reference Example 2 Synthesis of Compound (2)

A suspension of 1,4-dibromo-2,5-dimethylbenzene (154 g, 583 mmol) intetrahydrofuran (1.3 L) was cooled to −78° C., and a 1.53 Mbutyllithium-hexane solution (400 mL, 612 mmol) was added over 30minutes. The reaction solution was further stirred at the sametemperature for 1 hour, triisopropyl borate (170 mL, 734 mmol) was addedat once, and the mixture was stirred for 1 hour while the cooling bathwas removed and the temperature was gradually risen. After water (300mL) and 1N hydrochloric acid (650 mL) were added, the mixture wasextracted with ethyl acetate. The extract was washed with water and asaturated brine, dried and concentrated. The crystalline residue waswashed with hexane and filtered to obtain a compound (2)(115 g; yield86%).

Example 1 Synthesis of dihydroxy-(2-methylthio-5-pyridyl)borane (VIb′-1)

(First Step) Synthesis of 5-bromo-2-methylthio-pyridine (8)

A mixture of 2,5-dibromopyridine (7) (1100 g, 4.64 mol),tetrabutylammonium bromide (55 g, 0.037 equivalent) and a 15% aqueoussodium thiomethoxide solution (2387 g, 1.1 equivalent) was heated at 85to 90° C. for 3.5 hours. After the reaction mixture was cooled to 10°C., the resulting solid was filtered off. The organic layer was washedwith cold water (1 L) and concentrated to obtain the crude product (8)(985 g, yield 104%). The crude product (8) (908 g) was purified byrecrystallization using 2-propanol (2.1 L) and water (4.2 L) to obtain acompound (8) as crystals (831 g, yield 91.5%).

Mp: 39-40° C.

¹H-NMR (CDCl₃) δ 2.54 (s, 3H), 7.07 (dd, 1H, J=0.7, 8.6 Hz), 7.58 (dd,1H, J=2.4, 8.6 Hz), 8.49 (dd, 1H, J=0.7, 2.4 Hz).

Elemental Analysis for C₆H₆NSBr Calcd: C, 35.31; H, 2.96; N, 6.86; S,15.71; Br, 39.15. Found: C, 35.18; H, 3.03; N, 6.95; S, 15.56; Br,39.17; H₂O<0.2.

HPLC {Column: Cosmosil 5C18-AR 4.6×150 mm, Mobile phase:H₂O—CH₃CN-TFA=40-60-0.1, Rate: 1.0 mL/min, Detection (UV): 245 nm}.t_(R) 5.4 min, (7) t_(R) 4.3 min.

(Second Step) Synthesis of Compound VIb′-1

A solution of a 1.53 M butyllithium-hexane solution (500 mL, 765 mmol)in tetrahydrofuran (1.28 L) was cooled to −78° C., and a solution of thecompound (8) (142 g, 695 mmol) obtained in the first step intetrahydrofuran (400 mL) was added dropwise over 40 minutes. Thereaction solution was stirred at the same temperature for 30 minutes,and triisopropyl borate (195 mL, 834 mmol) was added dropwise over 30minutes. The mixture was stirred for 30 minutes while the cooling bathwas removed and the reaction temperature was gradually risen. Afterwater (320 mL) was added, the mixture was concentrated under reducedpressure, and the residue was diluted with water (710 mL) and isopropylether (210 mL). 3N hydrochloric acid (675 mL) was added dropwise whilestirring the reaction solution at room temperature. The precipitatedcrystals were filtered, washed with water and isopropyl ether, and driedto obtain a compound VIb′-1 (111 g; yield 95%).

Mp: 151-154° C.

Elemental Analysis for C₆H₈BNO₂S Calcd: C, 42.64; H, 4.77; N, 8.29; S,18.97 Found: C, 42.56; H. 4.88; N, 8.14; S, 18.79.

¹H-NMR(DMSO-d₆) δ 2.51 (s, 3H), 7.25 (dd, J=0.9, 8.1, 1H), 7.93 (dd,J=2.1, 8.1, 1H), 8.73 (dd, J=0.9, 2.1, 1H). HPLC {Column: Cosmosil5C18-AR 4.6X150 mm, Mobile phase: H₂O—CH₃CN-TFA=60-40-0.1, Rate: 1.0mL/min, Detection (UV): 245 nm}.

t_(R) 1.6 min, (8) t_(R) 14.9 min, (VIb′-1) t_(R) 2.8 min.

Example 2 Synthesis of Compound VIIb-1

(First Step) Synthesis of Compound (10)

To a solution of a compound (9) (4.41 g, 15.0 mmol) in dichloromethane(45 mL) were successively added 3-methyl-3-butenal (1.74 mL, 18.0 mmol),acetic acid (1.8 g, 30.0 mmol) and sodium triacetoxyborohydride (6.36 g,30.0 mmol), and the reaction solution was stirred for 15 hours. Afterthe reaction solution was poured into water, extracted with ethylacetate. The extract was washed with an aqueous sodium bicarbonatesolution and a saturated brine, dried and concentrated. The residue waspurified by silica gel chromatography (hexane-ethyl acetate 9:1) toobtain a compound (10) (4.09 g; yield 75%).

(Second Step) Synthesis of Compound VIIb-1

A solution of a compound (10) (2.4 g, 6.62 mmol) in tetrahydrofuran (24mL) was cooled to −78° C., and 1.53 M butyllithium (10.4 mL, 15.9 mmol)was added dropwise over 30 minutes. The reaction solution was furtherstirred for 2 hours, triisopropyl borate (5.5 mL, 23.8 mmol) was added,and the mixture was stirred for 30 minutes while the cooling bath wasremoved and a temperature was gradually risen to room temperature. Thereaction solution was poured into water and the mixture was extractedwith ethyl acetate. The extract was washed with an aqueous ammoniumchloride solution and a saturated brine, dried and concentrated. Thecrystalline residue was washed with hexane, and filtered to obtain acompound VIIb-1 (1.82 g; yield 87%).

¹H-NMR(DMSO-d₆) δ 1.70 (s, 3H), 1.72 (s, 3H), 2.12 (s, 3H), 2.63 (s,3H), 3.63 (br t, 2H), 5.28 (br t, 1H), 6.01 (br t, 1H), 6.37 (dd, J=2.1,13.2, 1H), 6.46 (dd, J=2.1, 8.4, 1H), 6.92 (s, 1H), 6.97 (t, J=8.4, 1H),7.77 (s, 1H)

Reference Example 3 Synthesis of Compound II-10

(First Step)

5-bromo-2-hydrazinopyridine (described in Journal of HeterocyclicChemistry, 1986 (23) 1071) (376 mg, 2.0 mmol) was heated at reflux inacetone (1 mL) and ethanol (4 mL) for 15 minutes. The reaction solutionwas concentrated to obtain a compound (11) (456 mg, quantitative) as thecrystalline residue.

(Second Step)

According to the same manner as that of Reference Example 1, a compoundII-10 (268 mg; yield 83%) was obtained from the compound (11) (175 mg,0.75 mmol) obtained in the first step and boronic acid (VIIb-1) (245 mg,0.75 mmol).

Reference Example 4 Synthesis of{2-Fluoro-2′,5′-dimethyl-4′-[6-(3-methyl-but-2-enyloxy)-pyridin-3-yl]-biphenyl-4-yl]}-(3-methyl-but-2-enyl)-carbamicacid chloromethyl ester (V-1)

The compound II-1 (444 mg, 1 mmol) synthesized in Reference Example 1was dissolved in anhydrous ether (40 mL) and ice-cooled, andchloromethyl chloroformate (194 mg, 1.5 mmol) and triethylamine (210 μL,1.5 mmol) were successively added while stirring under a nitrogenatmosphere, the ice bath was removed and the mixture was continued tostir for 4 hours. The precipitates in the reaction were filtered off.The organic layer was washed with water, dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure toobtain a compound V-1 (540 mg) as an oil.

Elemental Analysis for C₃₁H₃₄N₂O₃FCl; Calcd: C, 69.33; H, 6.38; N, 5.22;F, 3.54; Cl, 6.60. Found: C, 68.85; H, 6.42; N, 5.21; F, 3.58; Cl, 7.06.

Reference Example 5 Synthesis of(3-methyl-but-2-enyl)-(5-[2,3,5,6-tetramethyl-4-[6-(3-methyl-but-2-enyloxy)-pyridin-3-yl]-phenyl]-pyridin-2-yl)-carbamicacid chloromethyl ester (V-2)

A compound II-2 (300 mg, 0.658 mmol) synthesized according to the samemanner as that of Reference Example 1 was dissolved in anhydrous ether(30 mL) and ice-cooled, chloromethyl chloroformate (127 mg, 0.987 mmol)and triethylamine (128 μL, 0.921 mmol) were successively added whilestirring under a nitrogen atmosphere. The ice bath was removed and themixture was further stirred for 4 hours. The precipitates in thereaction mixture were filtered off. The organic layer was washed withwater, dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure to obtain a compound V-2 (360 mg).

¹H NMR (CDCl₃): δ H 1.67 (3H, s), 1.71 (3H, s), 1.8 (3H, s), 1.83 (3H,s), 1.97 (6H, s), 1.99 (6H, s), 4.65 (2H, d, J=6.9 Hz), 4.89 (2H, d,J=6.9 Hz), 5.36 (1H, bt, J=6.9 Hz), 5.59 (1H, bt, J=6.9 Hz), 5.88, (2H,s), 6.86 (1H, d, J=8.4 Hz), 7.4 (1H, ddd, J=8.7 Hz, 3.3 Hz, 2.7 Hz),7.52 (1H, ddd, J=8.4 Hz, 5.4 Hz, 2.4 Hz), 7.66 (1H, d, J=8.1 Hz), 7.97(1H, t, J=2.7 Hz), 8.26 (1H, dd, J=3 Hz, 2.4 Hz).

Elemental Analysis for C₃₂H₃₈N₃O₃Cl; Calcd: C, 70.12; H, 6.99; N, 7.67;Cl, 6.47. Found: C, 69.72; H, 7.39; N, 7.42; Cl, 7.

Reference Example 6 Synthesis of{2-fluoro-2′,5′-dimethyl-4′-[6-(3-methyl-but-2-enyloxy)-pyridin-3-yl]-biphenyl-4-yl]}-isopropyl-carbamicacid chloromethyl ester (V-3)

According to the same manner as that of Reference Example 4, a compoundV-3 (271 mg) was obtained from a compound II-9 (220 mg, 0.525 mmol) andchloromethyl chloroformate (101 mg, 0.788 mmol).

¹H NMR (CDCl₃): δ H 1.22 (6H, d, J=6.6 Hz), 1.79 (3H, s), 1.82 (3H, s),2.23 (3H, s), 2.29 (3H, s), 4.63 (1H, sep, J=6.6 Hz), 4.88 (2H, d, J=7.2Hz), 5.58 (1H, bt, J=7.2 Hz), 5.76 (2H, bs), 6.83 (1H, d, J=8.4 Hz),6.92-7.3 (5H, m), 7.61 (1H, dd, J=8.4 Hz, 2.4 Hz), 8.19 (1H, d, J=2.4Hz).

Elemental Analysis for C₂₉H₃₂N₂O₃FCl; Calcd: C, 68.16; H, 6.31; N, 5.48;F, 3.72; Cl, 6.94. Found: C, 66.81; H, 6.36; N, 5.44; F, 3.51; Cl, 7.82.

Reference Example 7 Synthesis of{3′-methoxy-2′,5′,6′-trimethyl-4′-[6-(3-metyl-but-2-enyloxy)-pyridin-3-yl]-biphenyl-4-yl]}-(3-methyl-but-2-enyl)-carbamicacid chloromethyl ester (V-4)

According to the same manner as that of Reference Example 4, a compoundV-4 (258 mg) was obtained from a compound II-4 (220 mg, 0.467 mmol) andchloromethyl chloroformate (90 mg, 0.7 mmol).

¹H NMR (CDCl₃): δ H 1.52 (3H, s), 1.72 (3H, s), 1.80 (3H, s), 1.83 (3H,s), 1.96 (6H, s), 2.07 (3H, s), 3.34 (3H, s), 4.32 (2H, d, J=7.2 Hz),4.89 (2H, d, J=6.9 Hz), 5.34 (1H, bt, J=7.2 Hz), 5.59 (1H, bt, J=6.9Hz), 5.81 (2H, bs), 6.84 (1H, d, J=8.7 Hz), 7.14-7.29 (4H, m), 7.55 (1H,dd, J=8.4 Hz, 2.4 Hz), 8.11 (1H, d, J=2.4 Hz).

Elemental Analysis for C₃₃H₃₉N₂O₄Cl; Calcd: C, 70.38; H, 6.98; N, 4.97;Cl, 6.3. Found: C, 69.76; H, 6.95; N, 5; Cl, 6.48.

Reference Example 8 Synthesis of{5-[3′-fluoro-2,5-dimethyoxy-3,6-dimethyl-4′-(3-methyl-but-2-enylamino)-biphenyl-4-yl]-pyridin-2-yl]}-(3-methyl-but-2-enyl-carbamicacid chloromethyl ester (V-6)

A compound II-3 (504 mg, 1 mmol) synthesized according to the samemanner as that of Reference Example 1 was dissolved in anhydrous ether(100 mL) and ice-cooled, chloromethyl chloroformate (154 mg, 1.2 mmol)and triethylamine (140 μL, 1 mmol) were successively added whilestirring under a nitrogen atmosphere, to react for 6 hours. The reactionwas treated as in Reference Example 4, and the crude product waspurified by silica gel chromatography (developing solvent: hexane-ethylacetate (1:2)) to obtain a compound V-6 (490 mg).

¹H NMR (CDCl₃): δ H 1.67 (3H, s), 1.7 (3H, s), 1.76 (3H, s), 1.79 (3H,s), 2.06 (3H, s), 2.07 (3H, s), 3.32 (3H, s), 3.35 (3H, s), 3.78 (2H, d,J=6.6 Hz), 3.88 (1H, bs,), 4.65 (2H, d, J=7.2 Hz), 5.36 (1H, bt, J=6.6Hz), 5.4 (1H, bt, J=6.9 Hz), 5.88 (2H, s), 6.77 (1H, t, J=8.1 Hz), 6.9-7(2H, m), 7.66 (2H, s), 8.39 (1H, s).

Elemental Analysis for C₃₃H₃₉N₃O₄FCl; Calcd: C, 66.49; H, 6.59; N, 7.05;F, 3.19, Cl, 5.95. Found: C, 66.24; H, 6.66; N, 7.13; F, 3.11; Cl, 6.28.

Reference Example 9 Synthesis of(5-{4′-[chloromethoxycarbonyl-(3-methyl-but-2-enyl)-amino]-3′-fluoro-2,5-dimethoxy-3,6-dimethyl-dimethyl-biphenyl-4-yl]}-pyridin-2-yl)-(3-methyl-but-2-enyl)-carbamicacid chloromethyl ester (V-7)

A compound II-3 (50 mg, 0.1 mmol) was dissolved in anhydrous ether (15mL) under a nitrogen atmosphere, chloromethyl chloroformate (51 mg, 0.5mmol) and triethylamine (66 μL, 0.475 mmol) were successively added,which was stirred at room temperature for 24 hours. The reaction wastreated as in Reference Example 4 to obtain a compound V-7 (58 mg).

¹H NMR (CDCl₃): δ H 1.51 (3H, s), 1.68 (6H, s), 1.7 (3H, s), 2.05 (3H,s), 2.07 (3H, s), 3.33 (3H, s), 3.36 (3H, s), 4.32 (2H, d, J=6.9 Hz),4.7 (2H, d, J=6.6 Hz), 5.3 (1H, bt, J=6.6 Hz), 5.36 (1H, bt, J=6.6 Hz),5.85 (2H, bs), 5.89 (2H, s), 7.06-7.3 (3H, m), 7.68 (2H, s), 8.4 (1H,s).

Elemental Analysis for C₃₅H₄₀N₃O₆FCl₂; Calcd: C, 61.05; H, 5.85; N, 6.1.Found: C, 60.98; H, 5.68; N, 6.09.

Example 3 Synthesis of succinamicacid-[{2-fluoro-2′,5′-dimethyl-4′-[6-(3-methyl-but-2-enyloxy)-pyridin-3-yl]-biphenyl-4-yl]}-(3-methyl-but-2-enyl)-carbamoyloxy]-methylester (I-1)

A suspension of succinamic acid (105 mg, 0.9 mmol) and potassiumcarbonate (62 mg, 0.45 mmol) in N,N-dimethylformamide (2 mL) was stirredat room temperature for 10 minutes. Then, a compound V-1 (161 mg, 0.3mmol) and potassium bromide (36 mg, 0.3 mmol) were successively added,which was vigorously stirred for 20 hours under an argon atmosphere. Thereaction mixture was diluted with ether (20 mL) and the insolublematerial was filtered off. The organic layer was washed with water,dried with anhydrous sodium sulfate, the solvent was distilled off underreduced pressure, and the material was purified by silica gel columnchromatography (hexane-ethyl acetate (4:1→1:2)) to obtain a compound I-1(116 mg, 63%).

The resulting compound has a higher melting point than that of a parentcompound II-1 and improvement in the physical properties was observed.

Mp: 107-109° C.

¹H NMR (CDCl₃): δ H 1.59 (3H, s), 1.73 (3H, s), 1.79 (3H, S), 1.82 (3H,s), 2.2 (3H, s), 2.29 (3H, s), 2.55 (2H, t, J=6.6 Hz), 2.76 (2H, t,J=6.6 Hz), 4.30 (2H, d, J=7.2 Hz), 4.88 (2H, d, J=7.2 Hz), 5.31 (1H, bt,J=7.2 Hz), 5.59 (2H, bt, J=7.2 Hz), 5.81 (2H, bs), 6.82 (1H, d, J=8.1Hz), 6.97-7.30 (5H, m), 7.6 (1H, dd, J=8.1 Hz, 2.4 Hz), 8.19 (1H, d,J=2.4 Hz).

Elemental Analysis for C₃₅H₄₀N₃O₆F; Calcd: C, 68.05; H, 6.53; N, 6.8; F,3.08. Found: C, 67.92; H, 6.49; N, 6.96; F, 3.13.

LSIMS: m/z 618 [M+H]⁺.

Example 4 Synthesis of carbamoyloxy-acetic acid[{2-fluoro-2′,5′-dimethyl-4′-[6-(3-methyl-but-2-enyloxy)-pyridin-3-yl]-biphenyl-4-y]}-(3-methyl-but-2-enyl)-carbamoyloxy]-methylester (I-3)

According to the same manner as that of Example 3, a compound V-1 (161mg, 0.3 mmol) and carbamoyloxyacetic acid (179 mg, 1.5 mmol) werereacted to obtain a compound I-3 (98 mg, 53%).

¹H NMR (CDCl₃): δ H 1.58 (3H, s), 1.73 (3H, s), 1.79 (3H, s), 1.82 (3H,s), 2.2 (3H, s), 2.28 (3H, s), 4.3 (2H, d, J=7.2 Hz), 4.66 (2H, s), 4.79(2H, bs), 4.88 (2H, d, J=6.9 Hz), 5.31 (1H, bt, J=7.2 Hz), 5.57 (1H, bt,J=6.9 Hz), 5.87 (2H, bs), 6.82 (1H, d, J=8.7 Hz), 7-7.30 (5H, m), 7.59(1H, dd, J=8.4, 2.4 Hz), 8.18 (1H, d, J=2.4 Hz).

Elemental Analysis for C₃₄H₃₈N₃O₇F; Calcd: C, 65.9; H, 6.18; N, 6.78; F,3.07. Found: C, 65.14; H, 6.47; N, 6.39; F, 2.93.

LSIMS: m/z 620 [M+H]⁺, 642 [M+Na]⁺.

Example 5 Synthesis of acetylamino-acetic acid[{2-fluoro-2′,5′-dimethyl-4′-[6-(3-methyl-but-2-enyloxy)-pyridin-3-yl]-biphenyl-4-yl]}-(3-methyl-but-2-enyl)-carbamoyloxy]-methylester (I-5)

According to the same manner as that of Example 3, a compound I-5 (305mg, 70%) was obtained from a compound V-1 (380 mg, 0.707 mmol) andN-acetylglycine (410 mg, 3.5 mmol).

¹H NMR (CDCl₃): δ H 1.57 (3H, s), 1.73 (3H, s), 1.79 (3H, s), 1.82 (3H,s), 2.05 (3H, s), 2.2 (3H, s), 2.28 (3H, s), 4.12 (2H, d, J=5.4 Hz),4.38 (2H, d, J=7.2 Hz), 4.88 (2H, d, J=6.9 Hz), 5.3 (1H, bt, J=7.2 Hz),5.57 (1H, bt, J=7.2 Hz), 5.86 (2H, bs), 5.93 (1H, bs), 6.82 (1H, d,J=8.1 Hz), 7-7.3 (5H, m), 7.59 (1H, dd, J=8.4, 2.4 Hz), 8.17 (1H, d,J=2.1 Hz).

Elemental Analysis for C₃₅H₄₀N₃O₆F; Calcd: C, 68.06; H, 6.53; N, 6.8; F,3.08. Found: C, 67.91; H, 6.58; N, 7; F, 2.91.

LSIMS: m/z 617 M⁺, 640 [M+Na]⁺.

Example 6 Synthesis of 4-acetylamino-4-carbamoyl-butyric acid[{2-fluoro-2′,5′-dimethyl-4′-[6-(3-methyl-but-2-enyloxy)-pyridin-3-yl]-biphenyl-4-yl}-(3-methyl-but-2-enyl)-carbamoyloxy]-methylester (I-6)

According to the same manner as that of Example 3, a compound I-6 (225mg, 65%) was obtained from a compound V-1 (269 mg, 0.5 mmol) andN-acetyl-L-isoglutamine (470 mg, 2.5 mmol).

Mp: 85-87° C.

¹H NMR (CDCl₃): δ H 1.57 (3H, s), 1.73 (3H, s), 1.8 (3H, s), 1.83 (3H,s), 1.95 (1H, m), 2.02 (3H, s), 2.19 (1H, M), 2.2 (3H, s), 2.28 (3H, s),2.49 (1H, m), 2.63 (1H, m), 4.12 (2H, d, J=5.4 Hz), 4.3(2H, d, J=7.2Hz), 4.54 (1H, td, J=8.1 Hz, 5.1 Hz), 4.89(2H, d, J=7.2 Hz), 5.31 (1H,bt, J=7.2 Hz), 5.33 (1H, bs), 5.58 (1H, bt, J=7.2 Hz), 5.8 (2H, bs),6.35 (1H, d, J=5.1 Hz), 6.37 (1H, bs), 6.84 (1H, d, J=8.4 Hz), 7.03-7.3(5H, m), 7.62 (1H, dd, J=8.4, 2.4 Hz), 8.18 (1H, d, J=2.4 Hz).

Elemental Analysis for C₃₈H₄₅N₄O₇F; Calcd: C, 66.26; H, 6.59; N, 8.13;F, 2.76. Found: C, 65.99; H, 6.59; N, 8.18; F, 2.71.

LSIMS: m/z 688 M⁺, 611 [M+Na]⁺.

Example 7 Synthesis of succinamic acid[(3-methyl-but-2-enyl)-(5-{2,3,5,6-tetramethyl-4-[6-(3-methyl-but-2-enyloxy)-pyridin-3-yl]-phenyl}-pyridin-2-yl)-carbamoyloxy]-methylester (I-19)

According to the same manner as that of Example 3, a compound I-13 (211mg, 74%) was obtained from a compound V-2 (250 mg, 0.456 mmol) andsuccinamic acid (267 mg, 2.28 mmol).

Mp: 124-126° C.

¹H NMR (CDCl₃): δ H 1.67 (3H, 5), 1.7 (3H, s), 1.8 (3H, s), 1.83 (3H,s), 1.97 (6H, s), 1.99 (6H, s), 2.56 (2H, t, J=6.6 Hz), 2.77 (2H, t,J=6.6 Hz), 4.63 (2H, d, J=6.9 Hz), 4.89 (2H, d, J=6.9 Hz), 5.31 (1H, bt,J=7.2 Hz), 5.35 (1H, bt, J=6.6 Hz), 5.37 (1H, bs), 5.59 (1H, bt, J=6.9Hz), 5.61 (1H, bs), 5.89 (2H, b), 6.86 (1H, d, J=8.7 Hz), 7.37-7.67 (3H,m), 7.97 (1H, s), 8.25 (1H, bs).

Elemental Analysis for C₃₆H₄₄N₄O₆; Calcd: C, 68.77; H, 7.05; N, 8.41.Found: C, 68.52; H, 7.04; N, 8.79.

Example 8 Synthesis of succinamic acid[{5-[3′-fluoro-2,5-dimethoxy-3,6-dimethyl-4′-(3-methyl-but-2-enylamino)-biphenyl-4-yl]-pyridin-2-yl}-(3-methyl-but-2-enyl)-carbamoyloxy]-methylester (I-37)

According to the same manner as that of Example 3, a compound I-25 (295mg, 69%) was obtained from a compound V-6 (375 mg, 0.63 mmol) andsuccinamic acid (368 mg, 3.15 mmol).

Mp: 136-138° C.

¹H NMR (CDCl₃): δ H 1.66 (3H, s), 1.69 (3H, s), 1.75 (3H, s), 1.79 (3H,s), 2.06 (3H, s), 2.07 (3H, s), 2.55 (2H, t, J=6.6 Hz), 2.76 (2H, t,J=6.6 Hz), 3.31 (3H, s), 3.35 (3H, s), 3.78 (2H, d, J=6.6 Hz), 4.63 (2H,d, J=6.9 Hz), 5.34 (1H, bt, J=6.6 Hz), 5.35 (1H, bs), 5.4 (1H, bt, J=6.6Hz), 5.61 (1H, bs), 5.88 (2H, s), 6.78 (1H, t, J=8.4 Hz), 6.93-6.97 (2H,m), 7.65 (2H, bs), 8.38 (1H, bs).

Elemental Analysis for C₃₇H₄₅N₄O₇F; Calcd: C, 65.66; H, 6.7; N, 8.28; F,2.81. Found: C, 65.39; H, 6.7; N, 8.07; F, 2.75.

Example 9 Synthesis of succinamic acid[(5-{4′-[(3-carbamoyl-propionyloxymethoxycarbonyl)-(3-methyl-but-2-enyl)-amino]3′-fluoro-3,6-dimethoxy-2,5-dimethyl-biphenyl-4-yl}-pyridin-2-yl)-(3-methyl-but-2-enyl)-carbamoyloxy]-methylester (I-55)

According to the same manner as that of Example 3, a compound I-37 (52mg, 76%) was obtained from a compound V-7 (55 mg, 0.08 mmol) andsuccinamic acid (94 mg, 0.8 mmol).

¹H NMR (CDCl₃): δ H 1.5 (3H, s), 1.67 (3H, s), 1.69 (3H, s), 1.7 (3H,s), 2.05 (3H, s), 2.06 (3H, s), 2.58 (4H, m), 2.77 (2H, m), 3.32 (3H,s), 3.35 (3H, s), 4.29 (2H, d, J=6.9 Hz), 4.64 (2H, d, J=6.9 Hz), 5.32(2H, m), 5.4 (2H, bs), 5.68 (2H, bs), 5.75 (2H, bs), 5.89 (2H, s),7.05-7.25 (3H, m), 7.67 (2H, s), 8.38 (1H, s).

Elemental Analysis for C₄₃H₅₂N₅O₁₂F; Calcd: C, 60.77; H, 6.17; N, 8.24;F, 2.24. Found: C, 59.57; H, 6.18; N, 7.98; F, 2.18.

Example 10 Synthesis of succinamic acid[{3′-methoxy-2′,5′,6′-trimethyl-4′-[6-(3-methyl-but-2-enyloxy)-pyridin-3-yl]-biphenyl-4-yl}-(3-methyl-but-2-enyl)-carbamoyloxy]-methylester (I-163)

According to the same manner as that of Example 3, a compound I-109 (218mg, 78%) was obtained from a compound V-4 (243 mg, 0.432 mmol) andsuccinamic acid (253 mg, 2.16 mmol).

Mp: 107-108° C.

¹H NMR (CDCl₃): δ H 1.53 (3H, s), 1.71 (3H, s), 1.83 (3H, s), 1.95 (6H,s), 2.06 (3H, s), 2.54 (2H, t, J=6.3 Hz), 2.75 (2H, t, J=6.3 Hz), 3.33(3H, s), 4.3 (2H, d, J=6.6 Hz), 4.88 (2H, d, J=6.9 Hz), 5.32 (1H, bt,J=6.6 Hz), 5.35 (1H, bs), 5.59 (1H, bt, J=6.9 Hz), 5.6 (1H, bs), 5.82(2H, bs), 6.84 (1H, d, J=8.7 Hz), 7.13-7.3 (4H, m), 7.55 (1H, dd, J=8.7Hz, 2.4 Hz), 8.11 (1H, d, J=2.4 Hz).

Elemental Analysis for C₃₇H₄₅N₃O₇; Calcd: C, 69.03; H, 7.05; N, 6.53.Found: C, 68.95; H, 7.02; N, 6.57.

Example 11 Synthesis of succinamic acid({2-fluoro-2′,5′-dimethyl-4′-[6-(3-methyl-but-2-enyloxy)-pyridin-3-yl]biphenyl-4-yl}-isopropyl-carbamoyloxy)-methylester (I-121)

According to the same manner as that of Example 3, a compound I-121 (122mg, 42%) was obtained from a compound V-3 (250 mg, 0.489 mmol) andsuccinamic acid (286 mg, 2.45 mmol).

¹H NMR (CDCl₃): δ H 1.21 (6H, d, J=6.6 Hz), 1.79 (3H, s), 1.82 (3H, s),2.22 (3H, s), 2.29 (3H, s), 2.54 (2H, t, J=6.3 Hz), 2.74 (2H, t, J=6.3Hz), 4.6 (1H, sep, J=6.6 Hz), 4.88 (2H, d, J=7.2 Hz), 5.58 (1H, bt,J=7.2 Hz), 5.35 (1H, bs), 5.6 (1H, bs), 5.76 (2H, bs), 6.82 (1H, d,J=8.4 Hz), 6.9-7.32 (5H, m), 7.6 (1H, dd, J=8.4 Hz, 2.4 Hz), 8.19 (1H,d, J=2.4 Hz).

Elemental Analysis for C₃₃H₃₈N₃O₆F; Calcd: C, 66.99; H, 6.47; N, 7.1; F,3.21. Found: C, 66.2; H, 6.58; N, 7; F, 3.05.

Example 12 Synthesis of 2-acetylamino-succinamic acid[{2-fluoro-2′,5′-dimethyl-4′-[6-(3-methyl-but-2-enyloxy)-pyridin-3-yl]-biphenyl-4-yl}-((E)-3-methyl-but-2-enyl)-carbamoyloxy]-methylester(I-13)

According to the same manner as that of Example 3, a compound I-13 (201mg, 50%) was obtained from a compound V-1 (322 mg, 0.6 mmol) andN-acetyl-L-aspartic acid (523 mg, 3 mmol).

Mp: 130-133° C.

¹H-NMR (CDCl₃): δ H 1.58 (3H, s), 1.74 (3H, s), 1.79 (3H, s), 1.83 (3H,s), 2.05 (3H, s), 2.21 (3H, s), 2.28 (3H, s), 2.77 (1H, dd, J=15.9, 4.2Hz), 3.01 (1H, dd, J=15.9, 4.5 Hz), 4.3 (2H, d, J=6.6 Hz), 4.86 (1H, t,J=4.2 Hz), 4.88 (2H, d, J=6.9 Hz), 5.31 (1H, bt, J=6.6 Hz), 5.48 (1H,bs), 5.58 (1H, bt, J=6.9 Hz), 5.75-5.92 (3H, bm), 6.8 (1H, d, J=7.5 Hz),6.83 (1H, d, J=8.7 Hz), 7.05-7.3 (5H, m), 7.61 (1H, dd, J=8.7, 2.1 Hz),8.18 (1H, d, J=2.1 Hz).

Elemental Analysis for C₃₇H₄₃N₄O₇F; Calcd: C, 65.86; H, 6.42; N, 8.3; F,2.82. Found: C, 65.57; H, 6.42; N, 8.27; F, 2.75.

ESIMS: m/z 675 [M+H]⁺, 697 [M+Na]⁺, 713 [M+K]⁺.

Example 13 Synthesis of 3-acetylamino-succinamic acid[{2-fluoro-2′,5′-dimethyl-4′-[6-(3-methyl-but-2-enyloxy)-pyridin-3-yl]-biphenyl-4-yl}-((E)-3-methyl-but-2-enyl)-carbamoyloxy]-methylester (I-14)

According to the same manner as that of Example 3, a compound I-14 (255mg, 67%) was obtained from a compound V-1 (300 mg, 0.56 mmol)andN-acetyl-L-isoasparagine(117 mg, 0.67 mmol).

Mp: 137-140° C.

¹H-NMR (CDCl₃): δ H 1.58 (3H, s), 1.73 (3H, s), 1.79 (3H, s), 1.82 (3H,s), 2.03 (3H, s), 2.2 (3H, s), 2.28 (3H, s), 2.69 (1H, dd, J=17.1, 6.9Hz), 3.05 (1H, dd, J=17.1, 4.5 Hz), 4.3 (2H, d, J=7.2 Hz), 4.85 (1H, t,J=4.2 Hz), 4.88 (2H, d, J=6.9 Hz), 5.31 (1H, bt, J=7.2 Hz), 5.55 (1H,bs), 5.57 (1H, bt, J=6.9 Hz), 5.8 (1H, bs), 5.82 (1H, bs), 6.55 (1H,bs), 6.82 (1H, d, J=8.4 Hz), 6.88 (1H, d, J=7.5 Hz), 7.01-7.3 (5H, m),7.6 (1H, dd, J=8.4, 2.4 Hz), 8.17 (1H, d, J=2.4 Hz).

Elemental Analysis for C₃₇H₄₃N₄O₇F; Calcd: C, 65.86; H, 6.42; N, 8.3; F,2.82. Found: C, 65.75; H, 6.4; N, 8.54; F, 2.74.

ESIMS: m/z 674 [M]⁺, 675 [M+H]⁺, 697 [M+Na]⁺.

Example 14 Synthesis of 2-acetylamino-4-carbamoyl-butyric acid[{2-fluoro-2′,5′-dimethyl-4′-[6-(3-methyl-but-2-enyloxy)-pyridin-3-yl]-biphenyl-4-yl}-((E)-3-methyl-but-2-enyl)-carbamoyloxy]-methylester (I-15)

According to the same manner as that of Example 6, a compound I-15 (156mg, 61%) was obtained from a compound V-1 (200 mg, 0.372 mmol) andN-acetyl-L-glutamine (351 mg, 1.86 mmol).

Mp: 110-113° C.

PMR (CDCl₃): δ H 1.58 (3H, s), 1.74 (3H, s), 1.8 (3H, s), 1.83 (3H, s),2.04 (3H, s), 2.2 (3H, s), 2.01-2.4 (4H, m), 4.29 (2H, d, J=7.2 Hz),4.62 (1H, td, J=8.1 Hz, 5.1 Hz), 4.88 (2H, d, J=7.2 Hz), 5.3 (1H, bt,J=7.2 Hz), 5.36 (1H, bs), 5.58 (1H, bt, J=7.2 Hz), 5.78 (1H, bs), 5.91(1H, bs), 6.1 (1H, bs), 6.81 (1H, d, J=8.4 Hz), 7.01-7.3 (5H, m), 7.6(1H, dd, J=8.4, 2.4 Hz), 8.18 (1H, d, J=2.4 Hz).

Elemental Analysis for C₃₈H₄N₄₅O₇F; Calcd: C, 66.26; H, 6.59; N, 8.13;F, 2.76. Found: C, 66.03; H, 6.62; N, 8.09; F, 2.7.

ESIMS: m/z 688 [M]⁺, 689 [M+H]⁺.

Example 15 Synthesis of (2-acetylamino-ethanoylamino)-acetic acid[{2-fluoro-2′,5′-dimethyl-4′-[6-(3-methyl-but-2-enyloxy)-pyridin-3-yl]-biphenyl-4yl]}-((E)-3-methyl-but-2-enyl)-carbamoyloxy]-methylester (I-16)

According to the same manner as that of Example 3, a compound I-16 (255mg, 63%) was obtained from a compound V-1 (322 mg, 0.6 mmol) andN-acetyl-glycylglycine(523 mg, 3 mmol).

The present compound has a higher melting point as compared with aparent compound II-1 and improvement in the physical properties was alsoobserved. In addition, the present compound has the advantage that itcan be simply formulated into a preparation because it does not generatestatic electricity.

Mp: 103-106° C.

¹H-NMR (CDCl₃): δ H 1.58 (3H, s), 1.73 (3H, s), 1.79 (3H, s), 1.82 (3H,s), 2.05 (3H, s), 2.2 (3H, s), 2.28 (3H, s), 3.98 (2H, d, J=5.4 Hz),4.12 (2H, d, J=5.4 Hz), 4.29 (2H, d, J=7.5 Hz), 4.88 (2H, d, 6.6 Hz),5.3 (1H, bt, J=7.5 Hz), 5.57 (1H, bt, J=6.6 Hz), 5.85 (2H, bs), 6.3 (1H,b), 6.62 (1H, b), 6.83 (1H, d, J=8.4 Hz), 6.95-7.3 (5H, m), 7.61 (1H,dd, J=8.4, 2.4 Hz), 8.18 (1H, d, J=2.4 Hz).

Elemental Analysis for C₃₇H₄₃N₄O₇F; Calcd: C, 65.86; H, 6.42; N, 8.3; F,2.82. Found: C, 65.5; H, 6.39; N, 8.22; F, 2.76.

ESIMS: m/z 675 [M+H]⁺, 697 [M+Na]⁺, 713 [M+K]⁺.

Example 16 Synthesis of 2-(2-acetylamino-propanoylamino-acetic acid[{2-fluoro-2′,-5′-dimethyl-4′-[6-(3-methyl-but-2-enyloxy)-pyridin-3-yl]-biphenyl-4-yl}-((E)-3-methyl-but-2-enyl)-carbamoyloxy]-methylester (I-17)

According to the same manner as that of Example 3, a compound I-17 (262mg, 76%) was obtained from a compound V-1 (269 mg, 0.5 mmol) andN-acetyl-DL-alanylglycine(108 mg, 0.6 mmol).

Mp: 79-82° C.

¹H-NMR (CDCl₃): δ H 1.38 (3H, d, J=7.2 Hz), 1.58 (3H, s), 1.74 (3H, s),1.79 (3H, s), 1.82 (3H, s), 2.02 (3H, S), 2.2 (3H, s), 2.28 (3H, s),4.05 (1H, dd, J=18.3, 4.5 Hz), 4.15 (1H, dd, J=18.3, 4.5 Hz), 4.3 (2H,d, J=7.2 Hz), 4.55 (1H, dq, J=7.5, 7.2 Hz), 4.88 (2H, d, 7.2 Hz), 5.3(1H, bt, J=7.2 Hz), 5.58 (1H, bt, J=7.2 Hz), 5.83 (2H, bs), 6.1 (1H, d,J=7.5 Hz), 6.72 (1H, t, J=4.5 Hz), 6.82 (1H, d, J=8.7 Hz), 7.02-7.3 (5H,m), 7.61 (1H, dd, J=8.7, 1.8 Hz), 8.17 (1H, d, J=1.8 Hz).

Elemental Analysis for C₃₈H₄₅N₄O₇F; Calcd: C, 66.26; H, 6.59; N, 8.13;F, 2.76. Found: C, 66.44; H, 6.73; N, 8.06; F, 2.6.

ESIMS: m/z 689 [M+H]⁺, 711 [M+Na]⁺, 727 [M+K]⁺.

Example 17 Synthesis of[2-(2-acetylamino-ethanoylamino)-ethanoylamino]-acetic acid[{2-fluoro-2′,5′-dimethyl-4′-[6-(3-methyl-but-2-enyloxy)-pyridin-3-yl]-biphenyl-4-yl}-((E)-3-methyl-but-2-enyl)-carbamoyloxy]-methylester (I-18)

According to the same manner as that of Example 3, a compound I-18 (314mg, 77%) was obtained from a compound V-1 (301 mg, 0.56 mmol) andN-acetyl-glycylglycylglycine (259 mg, 1.1 mmol).

Mp: 171-173° C.

¹H-NMR (CDCl₃): δ H 1.58 (3H, s), 1.74 (3H, s), 1.79 (3H, s), 1.83 (3H,s), 2.04 (3H, s), 2.2 (3H, s), 2.28 (3H, s), 3.94 (2H, d, J=5.7 Hz),4.01 (2H, d, J=6 Hz), 4.11 (2H, d, J=5.7 Hz), 4.29 (2H, d, J=6.9 Hz),4.88 (2H, d, 7.2 Hz), 5.3 (1H, bt, J=6.9 Hz), 5.57 (1H, bt, J=7.2 Hz),5.82 (2H, bs), 6.4 (1H, b), 6.83 (1H, d, J=8.4 Hz), 6.85 (1H, b),7.01-7.3 (5H, m), 7.6 (1H, dd, J=8.4, 2.4 Hz), 8.18 (1H, d, J=2.4 Hz).

Elemental Analysis for C₃₉H₄₆N₅O₈F; Calcd: C, 64.01; H, 6.34; N, 9.57;F, 2.6. Found: C, 63.88; H, 6.32; N, 9.74; F, 2.52.

ESIMS: m/z 732 [M+H]⁺, 754 [M+Na]⁺.

According to the same manner, compounds (I) were synthesized below. Thestructural formulas of intermediate compounds (II) and (V) and thepresent compounds (I) are shown below. Respective symbols in the Tablemean as follows:

Me: methyl

Et: ethyl

Ac: acetyl

nPr: n-propyl

iPr: i-propyl

TABLE 1

No

R⁸ R⁹ R¹⁰ R¹¹ X′ II-1

H Me Me H O II-2

Me Me Me Me O II-3

Me MeO MeO Me NH II-4

Me MeO Me Me O II-5

Me Me Me H O

TABLE 2

No R⁴ R⁵ R⁶ R⁷ R⁸ R⁹ R¹⁰ R¹¹

X′ Y Y′ II-6 H F H H H Me Me H

O CH₂CH═CMe₂ CH₂CH═CMe₂ II-7 H H H H H Me Me H

O CH₂CH═CMe₂ CH₂CH═CMe₂ II-8 H H H H Me MeO Me Me

O CH₂CH═CMe₂ CH₂CF₃ II-9 H F H H H Me Me H

O iPr CH₂CH═CMe₂  II-10 H F H H H Me Me H

NH CH₂CH═CMe₂ N═CMe₂ II-7 . . . 1.75(3H, s), 1.78(3H, s), 1.79(3H, s),1.80(3H, s), 1.98(3H, s), 2.18(6H, s), 2.28(3H, s), 3.75(2H, d, J=6.9),4.91(2H, d, J=6.9), 5.38(1H, m), 5.58(1H, m), 6.69(2H, d, J=8.4),6.87(1H, s), 7.15(1H, s), 7.21(2H, d, J=8.4) II-10 . . . foam; ¹H-NMR δ1.74(s, 3H), 1.78(s, 3H), 1.93(s, 3H), 2.08(s, 3H), 2.22(s, 3H), 2.27(s,3H), 3.72(br d, J=5.4, 2H), 3.77(br s, 1H), 5.35(m, 1H), 6.38(dd, J=2.4,12.3, 1H), 6.45(dd, J=2.4, 8.4, 1H), 7.06(t, J=8.4, 1H), 7.12(s, 1H),7.13(s, 1H), 7.27(d, J=8.4, 1H), 7.61(dd, J=2.1, 8.4, 1H), 7.68(br s,1H), 8.13(d, J=2.1, 1H)

TABLE 3

No R² R³

R⁸ R⁹ R¹⁰ R¹¹ X′ Y Y′ V-1 H H

H Me Me H O CH₂CH═CMe₂ CH₂CH═CMe₂ V-2 H H

Me Me Me Me O CH₂CH═CMe₂ CH₂CH═CMe₂ V-3 H H

H Me Me H O iPr CH₂CH═CMe₂ V-4 H H

Me MeO Me Me O CH₂CH═CMe₂ CH₂CH═CMe₂ V-5 H H

H Me Me H NH CH₂CH═CMe₂ N═CMe₂

TABLE 4

No R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ R⁹ R¹⁰ R¹¹ X V-6 H H F H H H Me MeO MeO Me NHV-7 H H F H H H Me MeO MeO Me NCOOCH₂Cl

TABLE 5

No R¹ R² R³ I-1  CH₂CH₂CONH₂ H H I-2  CH₂CH₂CONHMe H H I-3  CH₂OCONH₂ HH I-4  CH₂OCONHEt H H I-5  CH₂NHAc H H I-6  CH₂CH₂CH(CONH₂)NHAc H H I-7 CH₂CH(Me)CONH₂ H H I-8  CH₂CH₂CONHMe Me H I-9  CH(Me)OCONH₂ H H I-10CH₂OCONHEt Me Me I-11 CH₂NHAc Et H I-12 CH(Me)CH₂CH(CONH₂)NHAc Me H I-13CH(NHAc)CH₂CONH₂ H H I-14 CH₂CH(NHAc)CONH₂ H H I-15 CH(NHAc)(CH₂)₂CONH₂H H I-16 CH₂NHCOCH₂NHAc H H I-17 CH₂NHCOCH(Me)NHAc H H I-18CH₂(NHCOCH₂)₂NHAc H H

TABLE 6

No R¹ R² R³ I-19 CH₂CH₂CONH₂ H H I-20 CH₂CH₂CONHMe H H I-21 CH₂OCONH₂ HH I-22 CH₂OCONHEt H H I-23 CH₂NHAc H H I-24 CH₂CH₂CH(CONH₂)NHAc H H I-25CH₂CH(Me)CONH₂ H H I-26 CH₂CH₂CONHMe Me H I-27 CH(Me)OCONH₂ H H I-28CH₂OCONHEt Me Me I-29 CH₂NHAc Et H I-30 CH(Me)CH₂CH(CONH₂)NHAc Me H I-31CH(NHAc)CH₂CONH₂ H H I-32 CH₂CH(NHAc)CONH₂ H H I-33 CH(NHAc)(CH₂)₂CONH₂H H I-34 CH₂NHCOCH₂NHAc H H I-35 CH₂NHCOCH(Me)NHAc H H I-36CH₂(NHCOCH₂)₂NHAc H H

TABLE 7

No R¹ R² R³ X I-37 CH₂CH₂CONH₂ H H NH I-38 CH₂CH₂CONHEt H H NH I-39CH₂OCONH₂ H H NH I-40 CH₂OCONHMe H H NH I-41 CH₂NHAc H H NH I-42CH₂CH₂CH(CONH₂)NHAc H H NH I-43 CH₂CH(Me)CONH₂ H H NH I-44 CH₂CH₂CONHMeMe H NH I-45 CH(Me)OCONH₂ H H NH I-46 CH₂OCONHEt Me Me NH I-47 CH₂NHAcEt H NH I-48 CH(Me)CH₂CH(CONH₂)NHAc Me H NH I-49 CH(NHAc)CH₂CONH₂ H H NHI-50 CH₂CH(NHAc)CONH₂ H H NH I-51 CH(NHAc)(CH₂)₂CONH₂ H H NH I-52CH₂NHCOCH₂NHAc H H NH I-53 CH₂NHCOCH(Me)NHAc H H NH I-54CH₂(NHCOCH₂)₂NHAc H H NH

TABLE 8

No R1 R² R³ X I-55 CH₂CH₂CONH₂ H H NCOOCH₂OCOCH₂CH₂CONH₂ I-56CH₂CH₂CONHEt H H NCOOCH₂OCOCH₂CH₂CONHEt I-57 CH₂OCONH₂ H HNCOOCH₂OCOCH₂OCONH₂ I-58 CH₂OCONHMe H H NCOOCH₂OCOCH₂OCONHMe I-59CH₂NHAc H H NCOOCH₂OCOCH₂NHAc I-60 CH₂CH₂CH(CONH₂)NHAc H HNCOOCH₂OCOCH₂CH₂CH(CONH₂)NHAc I-61 CH₂CH(Me)CONH₂ H HNCOOCH₂OCOCH₂CH(Me)CONH₂ I-62 CH₂CH₂CONHMe Me H NCOOCH₂OCOCH₂CH₂CONHMeI-63 CH(Me)OCONH₂ H H NCOOCH₂OCOCH(Me)OCONH₂ I-64 CH₂OCONHEt Me MeNCOOCH₂OCOCH₂OCONHEt I-65 CH₂NHAc Et H NCOOCH₂OCOCH₂NHAc I-66CH(Me)CH₂CH(CONH₂)NHAc Me H NCOOCH₂OCOCH(Me)CH₂CH(CONH₂)NHAc I-67CH(NHAc)CH₂CONH₂ H H NCOOCH₂OCOCH(NHCOCH₃)CH₂CONH₂ I-68 CH₂CH(NHAc)CONH₂H H NCOOCH₂OCOCH₂CH(NHCOCH₃)CONH₂ I-69 CH(NHAc)(CH₂)₂CONH₂ H HNCOOCH₂OCOCH(NHCOCH₃)(CH₂)₂CONH₂ I-70 CH₂NHCOCH₂NHAc H HNCOOCH₂OCOCH₂NHCOCH₂NHCOCH₃ I-71 CH₂NHCOCH(Me)NHAc H HNCOOCH₂OCOCH₂NHCOCH(Me)NHCOCH₃ I-72 CH₂(NHCOCH₂)₂NHAc H HNCOOCH₂OCOCH₂(NHCOCH₂)₂NHCOCH₃

TABLE 9

No R¹ R² R³ I-73 CH₂CH₂CONH₂ H H I-74 CH₂CH₂CONHMe H H I-75 CH₂OCONH₂ HH I-76 CH₂OCONHEt H H I-77 CH₂NHAc H H I-78 CH₂CH₂CH(CONH₂)NHAc H H I-79CH₂CH(Me)CONH₂ H H I-80 CH₂CH₂CONHMe Me H I-81 CH(Me)OCONH₂ H H I-82CH₂OCONHEt Me Me I-83 CH₂NHAc Et H I-84 CH(Me)CH₂CH(CONH₂)NHAc Me H I-85CH(NHAc)CH₂CONH₂ H H I-86 CH₂CH(NHAc)CONH₂ H H I-87 CH(NHAc)(CH₂)₂CONH₂H H I-88 CH₂NHCOCH₂NHAc H H I-89 CH₂NHCOCH(Me)NHAc H H I-90CH₂(NHCOCH₂)₂NHAc H H

TABLE 10

No R¹ R² R³ I-91  CH₂CH₂CONH₂ H H I-92  CH₂CH₂CONHMe H H I-93  CH₂OCONH₂H H I-94  CH₂OCONHEt H H I-95  CH₂NHAc H H I-96  CH₂CH₂CH(CONH₂)NHAc H HI-97  CH₂CH(Me)CONH₂ H H I-98  CH₂CH₂CONHMe Me H I-99  CH(Me)OCONH₂ H HI-100 CH₂OCONHEt Me Me I-101 CH₂NHAc Et H I-102 CH(Me)CH₂CH(CONH₂)NHAcMe H I-103 CH(NHAc)CH₂CONH₂ H H I-104 CH₂CH(NHAc)CONH₂ H H I-105CH(NHAc)(CH₂)₂CONH₂ H H I-106 CH₂NHCOCH₂NHAc H H I-107 CH₂NHCOCH(Me)NHAcH H I-108 CH₂(NHCOCH₂)₂NHAc H H

TABLE 11

No R¹ R² R³ I-109 CH₂CH₂CONH₂ H H I-110 CH₂CH₂CONHMe H H I-111 CH₂OCONH₂H H I-112 CH₂OCONHEt H H I-113 CH₂NHAc H H I-114 CH₂CH₂CH(CONH₂)NHAc H HI-115 CH₂CH(Me)CONH₂ H H I-116 CH₂CH₂CONHMe Me H I-117 CH(Me)OCONH₂ H HI-118 CH₂OCONHEt Me Me I-119 CH₂NHAc Et H I-120 CH(Me)CH₂CH(CONH₂)NHAcMe H I-121 CH(NHAc)CH₂CONH₂ H H I-122 CH₂CH(NHAc)CONH₂ H H I-123CH(NHAc)(CH₂)₂CONH₂ H H I-124 CH₂NHCOCH₂NHAc H H I-125 CH₂NHCOCH(Me)NHAcH H I-126 CH₂(NHCOCH₂)₂NHAc H H

TABLE 12

No R¹ R² R³ I-127 CH₂CH₂CONH₂ H H I-128 CH₂CH₂CONHMe H H I-129 CH₂OCONH₂H H I-130 CH₂OCONHEt H H I-131 CH₂NHAc H H I-132 CH₂CH₂CH(CONH₂)NHAc H HI-133 CH₂CH(Me)CONH₂ H H I-134 CH₂CH₂CONHMe Me H I-135 CH(Me)OCONH₂ H HI-136 CH₂OCONHEt Me Me I-137 CH₂NHAc Et H I-138 CH(Me)CH₂CH(CONH₂)NHAcMe H I-139 CH(NHAc)CH₂CONH₂ H H I-140 CH₂CH(NHAc)CONH₂ H H I-141CH(NHAc)(CH₂)₂CONH₂ H H I-142 CH₂NHCOCH₂NHAc H H I-143 CH₂NHCOCH(Me)NHAcH H I-144 CH₂(NHCOCH₂)₂NHAc H H

TABLE 13

No R¹ R² R³ I-145 CH₂CH₂CONH₂ H H I-146 CH₂CH₂CONHMe H H I-147 CH₂OCONH₂H H I-148 CH₂OCONHEt H H I-149 CH₂NHAc H H I-150 CH₂CH₂CH(CONH₂)NHAc H HI-151 CH₂CH(Me)CONH₂ H H I-152 CH₂CH₂CONHMe Me H I-153 CH(Me)OCONH₂ H HI-154 CH₂OCONHEt Me Me I-155 CH₂NHAc Et H I-156 CH(Me)CH₂CH(CONH₂)NHAcMe H I-157 CH(NHAc)CH₂CONH₂ H H I-158 CH₂CH(NHAc)CONH₂ H H I-159CH(NHAc)(CH₂)₂CONH₂ H H I-160 CH₂NHCOCH₂NHAc H H I-161 CH₂NHCOCH(Me)NHAcH H I-162 CH₂(NHCOCH₂)₂NHAc H H

TABLE 14

No R¹ R² R³ I-163 CH₂CH₂CONH₂ H H I-164 CH₂CH₂CONHMe H H I-165 CH₂OCONH₂H H I-166 CH₂OCONHEt H H I-167 CH₂NHAc H H I-168 CH₂CH₂CH(CONH₂)NHAc H HI-169 CH₂CH(Me)CONH₂ H H I-170 CH₂CH₂CONHMe Me H I-171 CH(Me)OCONH₂ H HI-172 CH₂OCONHEt Me Me I-173 CH₂NHAc Et H I-174 CH(Me)CH₂CH(CONH₂)NHAcMe H I-175 CH(NHAc)CH₂CONH₂ H H I-176 CH₂CH(NHAc)CONH₂ H H I-177CH(NHAc)(CH₂)₂CONH₂ H H I-178 CH₂NHCOCH₂NHAc H H I-179 CH₂NHCOCH(Me)NHAcH H I-180 CH₂(NHCOCH₂)₂NHAc H H

TABLE 15

No R¹ R⁴ R⁵ R⁸ R⁹ R¹⁰ R¹¹ Y I-181 CH₂CH₂CONH₂ H F H Me Me H iPr I-182CH₂CH₂CONH₂ F H Me COOMe Me Me CH₂CH═CMe₂ I-183 CH₂CH₂CONH₂ H H H Et EtH CH₂CH═CMe₂ I-184 CH₂CH₂CONH₂ H Cl H OEt OEt H CH₂CH═CMe₂ I-185CH₂CH₂CONH₂ Cl H H COOMe Me H iPr I-186 CH₂CH₂CONH₂ H H Et OMe OMe EtCH₂CH═CMe₂ I-187 CH₂CH₂CONH₂ H F Et Et Et H CH₂CH═CMe₂ I-188 CH₂CH₂CONH₂F H Me Me OMe Me CH₂CH═CMe₂ I-189 CH₂CH₂CONH₂ H H Me Me COOMe MeCH₂CH═CMe₂ I-190 CH₂CH₂CONH₂ H Cl H OMe OMe OH CH₂CH═CMe₂ I-191CH₂CH₂CONH₂ Cl H Me Me Me OH CH₂CH═CMe₂ I-192 CH₂CH₂CONH₂ H H Me Me OHMe CH₂CH═CMe₂ I-193 CH₂CH₂CONHMe H F H OMe OMe H iPr I-194 CH₂CH₂CONHMeF H Me COOMe Me Me CH₂CH═CMe₂ I-195 CH₂CH₂CONHMe H H H Et Et HCH₂CH═CMe₂ I-196 CH₂CH₂CONHMe H Cl H OEt OEt H CH₂CH═CMe₂ I-197CH₂CH₂CONHMe Cl H H COOMe Me H CH₂CH═CMe₂ I-198 CH₂CH₂CONHMe H H Et OMeOMe Et CH₂CH═CMe₂ I-199 CH₂CH₂CONHMe H F Et Et Et H CH₂CH═CMe₂ I-200CH₂CH₂CONHMe F H Me Me OMe Me CH₂CH═CMe₂ I-201 CH₂CH₂CONHMe H H Me MeCOOMe Me iPr I-202 CH₂CH₂CONHMe H Cl H OMe OMe OH CH₂CH═CMe₂ I-203CH₂CH₂CONHMe Cl H Me Me Me OH CH₂CH═CMe₂ I-204 CH₂CH₂CONHMe H H Me Me OHMe CH₂CH═CMe₂

TABLE 16

No R¹ R⁴ R⁵ R⁸ R⁹ R¹⁰ R¹¹ I-205 CH₂OCONH₂ H F H OMe OMe H I-206CH₂OCONH₂ F H Me COOMe Me Me I-207 CH₂OCONH₂ H H H Et Et H I-208CH₂OCONH₂ H Cl H OEt OEt H I-209 CH₂OCONH₂ Cl H H COOMe Me H I-210CH₂OCONH₂ H H Et OMe OMe Et I-211 CH₂OCONH₂ H F Et Et Et H I-212CH₂OCONH₂ F H Me Me OMe Me I-213 CH₂OCONH₂ H H Me Me COOMe Me I-214CH₂OCONH₂ H Cl H OMe OMe OH I-215 CH₂OCONH₂ Cl H Me Me Me OH I-216CH₂OCONH₂ H H Me Me OH Me I-217 CH₂NHAc H F H OMe OMe H I-218 CH₂NHAc FH Me COOMe Me Me I-219 CH₂NHAc H H H Et Et H I-220 CH₂NHAc H Cl H OEtOEt H I-221 CH₂NHAc Cl H H COOMe Me H I-222 CH₂NHAc H H Et OMe OMe EtI-223 CH₂NHAc H F Et Et Et H I-224 CH₂NHAc F H Me Me OMe Me I-225CH₂NHAc H H Me Me COOMe Me I-226 CH₂NHAc H Cl H OMe OMe OH I-227 CH₂NHAcCl H Me Me Me OH I-228 CH₂NHAc H H Me Me OH Me

TABLE 17

No R¹ R⁴ R⁵ R⁸ R⁹ R¹⁰ R¹¹ I-229 CH₂NHCOC₂H₅ H F H OMe OMe H I-230CH₂CSNH₂ F H Me COOMe Me Me I-231 CH₂OCH₂CH₂OH H H H Et Et H I-232CH₂OMe H F H OEt OEt H I-233 CH₂OCH₂CH₂OMe F H H COOMe Me H I-234CH₂COCH₃ H H Et OMe OMe Et I-235 CH₂COC₂H₅ H F Et Et Et H I-236CH₂OCOCH₃ F H Me Me OMe Me I-237 CH₂OCOC₂H₅ H H Me Me COOMe Me I-238CH₂NHOH H F H OMe OMe OH I-239 CH₂NHCONH₂ F H Me Me Me OH I-240CH₂NHCSNH₂ H H Me Me OH Me I-241 CH₂NHSO₂Me H F H OMe OMe H I-242CH₂N(SO₂Me)₂ F H Me COOMe Me Me I-243 CH₂SO₂NH₂ H H H Et Et H I-244CH₂SOMe H F H OEt OEt H I-245 CH₂SO₂Me F H H COOMe Me H I-246CH₂OCH₂CONH₂ H H Et OMe OMe Et I-247 CH₂OCH₂CONMe₂ H F Et Et Et H I-248CH₂SO₂NMe₂ F H Me Me OMe Me I-249 CH₂PO(OMe)₂ H H Me Me COOMe Me I-250CH₂NHCSNHEt H F H OMe OMe OH I-251 CH₂CH═NNHCONH₂ F H Me Me Me OH I-252CH₂CH═NNHCSNH₂ H H Me Me OH Me I-253 CH₂CH═NNHSO₂Me H F H OMe OMe HI-254 CH₂-1,2,3-Triazol-5-yl F H Me COOMe Me Me I-255 CH₂-Tetrazol-1-ylH H H Et Et H

TABLE 18

No R¹ R⁴ R⁵ R⁸ R⁹ R¹⁰ R¹¹ I-256 CH₂NHCOC₂H₅ H F H Me Me H I-257 CH₂CSNH₂F H Me COOMe Me Me I-258 CH₂OCH₂CH₂OH H H H Et Et H I-259 CH₂OMe H F HOEt OEt H I-260 CH₂OCH₂CH₂OMe F H H COOMe Me H I-261 CH₂COCH₃ H H Et OMeOMe Et I-262 CH₂COC₂H₅ H F Et Et Et H I-263 CH₂OCOCH₃ F H Me Me OMe MeI-264 CH₂OCOC₂H₅ H H Me Me COOMe Me I-265 CH₂NHOH H F H OMe OMe OH I-266CH₂NHCONH₂ F H Me Me Me OH I-267 CH₂NHCSNH₂ H H Me Me OH Me I-268CH₂NHSO₂Me H F H OMe OMe H I-269 CH₂N(SO₂Me)₂ F H Me COOMe Me Me I-270CH₂SO₂NH₂ H H H Et Et H I-271 CH₂SOMe H F H OEt OEt H I-272 CH₂SO₂Me F HH COOMe Me H I-273 CH₂OCH₂CONH₂ H H Et OMe OMe Et I-274 CH₂OCH₂CONMe₂ HF Et Et Et H I-275 CH₂SO₂NMe₂ F H Me Me OMe Me I-276 CH₂PO(OMe)₂ H H MeMe COOMe Me I-277 CH₂NHCSNHEt H F H OMe OMe OH I-278 CH₂CH═NNHCONH₂ F HMe Me Me OH I-279 CH₂CH═NNHCSNH₂ H H Me Me OH Me I-280 CH₂CH═NNHSO₂Me HF H OMe OMe H I-281 CH₂CH₂-1,2,3-Triazol-5-yl F H Me COOMe Me Me I-282CH₂CH₂-Tetrazoly-1-yl H H H Et Et H

Test Example 1 IgE Antibody Production Inhibiting Effects AgainstAnti-ovalbumin (OVA)

1) Animal

BALB/c mice (female, 8-10 weeks old) and Wistar rats (female, 8-10 weeksold) purchased from Japan SLC (Shizuoka) were used.

2) Method of Immunization

0.2 mL of a solution obtained by suspending 2 μg of ovalbumin (OVA) and2 mg of aluminium hydroxide gel in a physiological saline was injectedin a BALB/c mouse intraperitoneally to immunize it. After ten days,blood was taken from the heart, serum was separated, and stored at −40°C. until the IgE antibody titer was measured.

3) Compound

The present compound and its parent compound (II-1) were dissolved orsuspended in methylcellulose, and diluted 20-fold with a neutral oilMigriol 812 to obtain a solution, which was orally administered at anamount of 0.1 mL per mouse (dose 10, 40 mg/kg). Administration wascarried out for consecutive 10 days from an immunization day to the daybefore a blood collection day.

4) Measurement of Anti-OVA IgE Antibody Titer (PCA Titer)

The resulting mouse serum was prepared into a 2-fold dilution seriesusing a physiological saline, each 50 μl of which was injected to apre-haircut Wistar rat intracutaneously at a back. After 24 hours, 0.5mL of a physiological saline containing 1 mg of OVA and 5 mg of EvansBlue pigment was injected intravenously to induce passive cutaneousanaphylaxis reaction (PCA). After 30 minutes, a maximum dilution rate ofthe serum showing PCA positive reaction of a pigment spot having adiameter of 5 mm or more was determined, and Log₂ of its dilution ratewas adopted as a PCA titer. For example, when a serum becomes PCAreaction positive until 2⁷-fold dilution, an anti-OVA IgE antibody titerof the mouse is 7. The results are shown in Table 19.

TABLE 19 3 mg/Kg 10 mg/Kg 40 mg/Kg II-1 — 6.7 0.8 I-1 7.0 0.8 — I-6 —1.8 — I-13 — <0 — I-15 — 0 — I-16 — <0 —

The present compound exhibits the higher activity as compared with acompound (II-1), and it can be seen that the present compoundeffectively acts as a prodrug.

Test Example 2 Oral Absorption Test

The present compound (I-1) was ground with an agate mortar, which wasprepared into an aqueous suspension having the concentration of 10 mg/mLusing a 0.5% aqueous methylcellulose solution as a vehicle. Eachcompound was orally administered to a Jcl:SD male rat (10 weeks old, 18hours fasting) as a parent compound at a rate of 20 mg/kg. 0.5, 1, 2, 4,6, 8 and 24 hours after administration, 0.3 mL of blood was taken from acannula inserted in rat jugular in advance. The blood was centrifuged toobtain a plasma. 0.5 mL of a mixed solution of methanol and acetonitrile(1/1 (w/w)) was added to 0.1 mL of the plasma, proteins were removedtherefrom, followed by centrifugation. The supernatant was used as aHPLC sample. The HPLC conditions for the compound are shown in Table 20.

TABLE 20 Column Develosil ODS-UG-5 (4.6 × 150 mm) Mobile phase 0.1 MNaClO₄:MeOH = 12:88 Rate (mL/min) 1.0 mL/min Detection UV:255 nmRetention time 15.5 min (min)

The C_(max) was 2.50 μg/mL, and the AUC was 32.03 μg·hr/mL. The timecourse of the plasma concentration after oral administration is shown inFIG. 1.

The present compound (I-1) was not detected in the circulating plasma of(I-1)-orally administered rat, and only a parent compound (II-1) wasobserved, exhibiting the high concentration in the plasma. The compound(I-1) has the high oral absorbability, and it can be seen that it isuseful as a prodrug. Further, as described above, a melting pointthereof was elevated and improvement in the physical properties wasattained.

Test Example 3 Oral Absorption Test

The oral absorbabilities of the present compound (I-163) and its parentcompound (II-4) were measured as in Test Example 2. The HPLC conditionsare shown in Table 21.

TABLE 21 I-163 II-4 Column Develosil ODS-UG-5 Develosil ODS-UG-5 (2.0 ×150 mm) (2.0 × 150 mm) Mobile phase H₂O:MeOH = 12:88 H₂O:MeOH = 12:88Rate (mL/min) 0.2 mL/min 1.0 mL/min Detection UV:255 nm UV:255 nmRetention time 14.5 min 6.6 min (min)

The C_(max) of the parent compound (II-4) was 0.11 μg/mL, and the AUCwas 1.64 μg·hr/mL. The C_(max) of the present compound (I-163) was 1.08μg/mL, and the AUC was 12.38 μg·hr/mL. The time course of the plasmaconcentration after oral administration is shown in FIG. 2. The presentcompound showed the extremely high oral absorbability as compared withthe parent compound.

Test Example 4 Oral Absorption Test

The oral absorbabilities of the present compound (I-16) and its parentcompound (II-1) were measured as in Test Example 2 using a non-fastingrat. The HPLC conditions are shown in Table 22.

TABLE 22 I-16 II-1 Column Develosil ODS-UG-5 Develosil ODS-UG-5 (2.0 ×150 mm) (2.0 × 150 mm) Mobile phase H₂O/MeOH = 12/88 H₂O/MeOH = 12/88Rate (mL/min) 0.2 mL/min 0.2 mL/min Detection UV:255 nm UV:255 nmRetention time 6.7 min 16.0 min (min)

The compound (I-16) was not detected in the circulating plasma of thepresent compound (I-16)-orally administered rat, only the parentcompound (II-1) was observed, exhibiting the high concentration in theplasma. The C_(max) of the (II-1) was 6.13 μg/mL, and the AUC was 57.31μg·hr/mL. The C_(max) of the (I-16) was 16.02 μg/mL, and the AUC was165.52 μg·hr/mL. The time course of the plasma concentration after oraladministration is shown in FIG. 3.

Preparation Example 1 Tablets Compound (I) 15 mg Starch 15 mg Lactose 15mg Crystalline cellulose 19 mg Polyvinyl alcohol 3 mg distilled water 30ml Calcium stearate 3 mg

Ingredients other than calcium stearate were mixed uniformly, ground andgranulated, dried, and prepared into granules having a suitable size.Then, calcium stearate was added, which was compression-molded to obtaintablets.

Industrial Applicability

The compound (I) shows the high oral absorbability and its active formof a compound (II) show the strong immunosuppressive activity and/orantiallergic activity. Accordingly, the present compound is very usefulas an immunosuppressive agent and/or an antiallergic agent.

What is claimed is:
 1. A compound represented by the formula (I):

wherein is —N(COOCR³R²OCOR¹)—, and X′ is —O—, R¹ is lower alkylsustituted with 1 or 2 groups selected from the group consisting of—CONH₂, —CONHCH₃, —CONHC₂H₅, —OCONH₂, —OCONHCH₃, —OCONHC₂H₅,—(NHCOCRR′)mNHCOCH₃, —(NHCOCRR′)mNHCOC₂H₅, —CSNH₂, —(OCH₂CH₂)nOH, —OCH₃,—(OCH₂CH₂)nOCH₃, —COCH₃, —COC₂H₅, —OCOCH₃, —OCOC₂H₅, —NHOH, —NHCONH₂,—NHCSNH₂, —NHSO₂CH₃, —N(CO₂CH₃)₂, —SO₂NH₂, —SOCH₃, —SO₂CH₃, —OCH₂CONH₂,—OCH₂CON(CH₃)₂, —SO₂N(CH₃)₂, —PO(OCH₃)₂, —NHCSNHC₂H₅, —CH═NNHCONH₂,—CH═NNHCSNH₂, or —CH═NNHSO₂CH₃, triazolyl and tetrazolyl (wherein R andR′ are each independently hydrogen or lower alkyl, m is an integer of 0to 2, and n is an integer of 1 or 2), R² and R³ are each independentlyhydrogen or lower alkyl, Y and Y′ are each independently hydrogen,optionally substituted lower alkyl, optionally substituted loweralkenyl, optionally substituted lower alkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkenyl, optionally substitutedlower alkoxycarbonyl, optionally substituted, sulfamoyl, optionallysubstituted amino, optionally substituted aryl or optionally substituted5-membered or 6-membered heterocycle, ring A, and ring B are each anoptionally substituted benzene ring, and ring C is pyridine, both V¹ andV² are a single bond, or a pharmaceutically acceptable salt or a solvatethereof.
 2. A compound represented by the formula (II):

wherein X is —N(COOCR³R²OCOR¹)—, and X′ is —O—, Y and Y′ are eachindependently optionally substituted lower alkyl, optionally substitutedlower alkenyl or optionally substituted lower alkynyl, R¹, R² and R³have the same meanings as those for claim 1, ring A is optionallysubstituted benzene ring and ring C is pyridine, R⁸, R⁹, R¹⁰ and R¹¹,are each independently hydrogen, halogen, hydroxy, optionallysubstituted lower alkyl, optionally substituted lower alkoxy, optionallysubstituted lower alkenyl, optionally substituted lower alkenyloxy,optionally substituted cycloalkyloxy, optionally substituted acyloxy,carboxy, optionally substituted lower alkoxycarbonyl, optionallysubstituted lower alkenyloxycarbonyl, optionally substituted loweralkylthio, optionally substituted lower alkenylthio, optionallysubstituted amino, optionally substituted carbamoyl, guanidino, nitro,optionally substituted lower alkylsulfonyl, optionally substituted loweralkylsulfonyloxy, optionally substituted arylsultonyl or optionallysubstituted arylsulfonyloxy, or a pharmaceutically acceptable salt or asolvate thereof.
 3. A compound represented by the formula (III):

wherein X is —N(COOCR³R²OCOR¹)—, X′ is —O—, Y and Y′ are eachindependently optionally substituted lower alkyl or optionallysubstituted lower alkenyl, R¹, R² and R³ have the same meanings as thosefor claim 1, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independentlyhydrogen, halogen, hydroxy, optionally substituted lower alkyl,optionally substituted lower alkoxy, optionally substituted loweralkenyl, optionally substituted lower alkenyloxy, carboxy, optionallysubstituted lower alkoxycarbonyl or optionally substituted amino, ring Cis pyridine, optionally substituted with lower alkyl, or apharmaceutically acceptable salt or a solvate thereof.
 4. The compoundaccording to any one of claims 1 to 3, wherein R¹ is C1 to C3 alkylsubstituted with 1 or 2 groups selected from the group consisting of—CONH₂, —OCONH₂ and —(NHCOCRR′)mNHCOCH₃, a pharmaceutically salt or asolvate thereof.
 5. The compound according to claim 3, wherein R⁴ and R⁵are each independently hydrogen or halogen, or a pharmaceuticallyacceptable salt or a solvate thereof.
 6. The compound according to claim3, wherein R⁶ and R⁷ are both hydrogen, or a pharmaceutically acceptablesalt or a solvate thereof.
 7. The compound according to claim 2 or 3,wherein R⁸ and R¹¹ are each independently hydrogen, hydroxy or loweralkyl, a pharmaceutically acceptable salt or a solvate thereof.
 8. Thecompound according to claim 2 or 3, wherein R⁹ and R¹⁰ are eachindependently lower alkyl, lower alkoxy or lower alkoxycarbonyl, or apharmaceutically acceptable salt or a solvate thereof.
 9. The compoundaccording to claim 3, wherein X is —N(COOCHR²OCOR¹)—, X′ is —O—, R¹ isC1 to C3 alkyl substituted with 1 or 2 groups selected from the groupconsisting of —CONH₂, —OCONH₂ and —(NHCOCRR′)mNHCOCH₃, R² and R³ arehydrogen or C1 to C3 alkyl, Y and Y′ are each independently lower alkyloptionally substituted with halogen or lower alkenyl optionallysubstituted with halogen, R⁴ and R⁵ are each independently hydrogen orhalogen, R⁶ and R⁷ are both hydrogen, R⁸ and R¹¹ are each independentlyhydrogen, hydroxy or lower alkyl, R⁹ and R¹⁰ are each independentlylower alkyl, lower alkoxy or lower alkoxycarbonyl, and ring C ispyridine optionally substituted with lower alkyl, or a pharmaceuticallyacceptable salt or a solvate thereof.
 10. The compound according to anyone of claims 1, 2, 3 and 9, wherein Y and Y′ are both prenyl, or apharmaceutically acceptable salt or a solvate thereof.
 11. The compoundaccording to claim 3 or 4, wherein ring C is

R⁴ and R⁵ are each independently hydrogen, halogen or lower alkoxy, R⁶and R⁷ are each independently hydrogen, halogen or lower alkyl, R⁸ andR¹¹ are both lower alkyl, or one of them is lower alkyl and the other ishydrogen or lower alkoxy, R⁹ and R¹⁰ are both hydrogen, lower alkyl orlower alkoxy, and one of —X—Y and —X′—Y′ is—N(COOCR³R²OCOR¹)-Alk(wherein Alk is optionally substituted lower alkylor optionally substituted lower alkenyl), and the other is prenyloxy orprenylamino, or a pharmaceutically acceptable salt or a solvate thereof.12. The compound according to claim 3 or 4, wherein ring C is

wherein X has the same meaning as that for claim 3, or a salt or asolvate thereof.
 13. A pharmaceutical composition, which comprises acompound as defined in any one of claims 1 to 3, or a pharmaceuticallyacceptable salt or a solvate thereof.